INDEX

A

Accreditation, 198-199, 243-245, 394

Acetaminophen, 67

Acne research, 80, 185

Adolescent Medicine HIV/AIDS Research Network, 262, 264

Adolescents. See also Assent;

Emancipated minors;

Mature minors;

Wards of the state

comprehension of research participation, 183-185

consent process for, 8, 9, 154, 156, 171-172, 192-194, 200-201, 204, 206, 207, 322

decisional maturity, 186, 325

defined, 62, 64-66

developmental physiology, 62, 65-66

enrolled in clinical trials, 87

medical examination components, 124

payment for participation, 10, 213, 218-219, 227

pharmacokinetics in, 70

privacy issues, 158, 187, 205, 323, 327

runaways and throw-aways, 200

waiver of parental permissions, 354-362

Adverse events. See also Harm

defined, 106, 394

in ethical principles, 46

examples of, 28-29, 82, 234

monitoring, 37, 105, 106-107

in placebo-controlled trials, 142

reporting requirements, 105, 106-107, 231

serious, 398

Advisory Committee on Human Radiation Experiments, 48, 164, 165

Advocates and advocacy for participants, 154-155, 159, 208, 328-329, 339

Age of consent

for medical care, 4, 94, 156, 325-326, 354-362

for research participation, 94, 326-328

Age of majority

defined, 394

state laws, 94, 104, 322-323, 342-343

Agency for Health Research and Quality, 90

AIDS, 78

Alabama, 104, 325, 340, 342, 344, 347, 354, 364-365

Alaska, 340, 342, 344, 347, 354

Albert Einstein College of Medicine, 271

Alexander, Leo, 46 n.9, 47 n.10

Allergy and Asthma Network, 194, 221

Allergy research, 80

Altruism, 164, 165, 167, 168, 170, 191

American Academy of Pediatrics, 60, 65-66, 120, 140, 161, 221, 251



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Ethical Conduct of Clinical Research Involving Children INDEX A Accreditation, 198-199, 243-245, 394 Acetaminophen, 67 Acne research, 80, 185 Adolescent Medicine HIV/AIDS Research Network, 262, 264 Adolescents. See also Assent; Emancipated minors; Mature minors; Wards of the state comprehension of research participation, 183-185 consent process for, 8, 9, 154, 156, 171-172, 192-194, 200-201, 204, 206, 207, 322 decisional maturity, 186, 325 defined, 62, 64-66 developmental physiology, 62, 65-66 enrolled in clinical trials, 87 medical examination components, 124 payment for participation, 10, 213, 218-219, 227 pharmacokinetics in, 70 privacy issues, 158, 187, 205, 323, 327 runaways and throw-aways, 200 waiver of parental permissions, 354-362 Adverse events. See also Harm defined, 106, 394 in ethical principles, 46 examples of, 28-29, 82, 234 monitoring, 37, 105, 106-107 in placebo-controlled trials, 142 reporting requirements, 105, 106-107, 231 serious, 398 Advisory Committee on Human Radiation Experiments, 48, 164, 165 Advocates and advocacy for participants, 154-155, 159, 208, 328-329, 339 Age of consent for medical care, 4, 94, 156, 325-326, 354-362 for research participation, 94, 326-328 Age of majority defined, 394 state laws, 94, 104, 322-323, 342-343 Agency for Health Research and Quality, 90 AIDS, 78 Alabama, 104, 325, 340, 342, 344, 347, 354, 364-365 Alaska, 340, 342, 344, 347, 354 Albert Einstein College of Medicine, 271 Alexander, Leo, 46 n.9, 47 n.10 Allergy and Asthma Network, 194, 221 Allergy research, 80 Altruism, 164, 165, 167, 168, 170, 191 American Academy of Pediatrics, 60, 65-66, 120, 140, 161, 221, 251

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Ethical Conduct of Clinical Research Involving Children American Cancer Society, 80 American Law Institute, 325 n.8 American Medical Association (AMA), 45 n.7, 46 n.9, 223 American Pediatric Society, 254 Anesthesia research, 168, 183 Antibiotics, 50, 76 Anticancer agents, 66, 71-72, 73, 80, 106 Anticonvulsants, 69 Antidepressants, 27, 60 Antihistamines, 71 Arizona, 340, 342, 344, 347, 354 Arkansas, 340, 342, 344, 347, 354 Arthritis, 77 Assent. See also Consent process; Informed consent; Parental permission age appropriateness of process, 7, 8, 156, 171-172, 173, 179-180, 183-185, 192-193, 205-207 cognitive development and, 179-180, 205-206 comprehension of research participation and, 7, 28, 42, 131-132, 181-193, 205-206 defined, 51 n.13, 101, 146-147, 156, 327, 394 discretion in documenting, 207 ethical principles, 40-41, 50, 84, 148, 192 experience of illness and, 131-132, 189-190 forms, 193, 206, 207 historical evolution of policies, 50, 51 n.13 information to be provided, 206 legal requirements for, 3, 104, 151-153, 156-157, 182, 191, 204 motivations for, 164, 165, 167, 168, 170, 191 “mutual pretense” process and, 191 parental influence, 187, 190-191, 204-205 payment for participation and, 189, 211 for placebo-controlled trials, 140 procedures for seeking, 148, 149-151, 156, 172-173, 205-207 purpose of research and, 171 recommended improvements in, 20, 203-205 waiver of, 156 withdrawal from trials, 183, 187-188, 190, 197 Association for the Accreditation of Human Research Protection Programs, 244 Association of American Medical Colleges, 244 n.2 Association of American Universities, 244 n.2 Association of Medical School Pediatric Department Chairs, 221 Assurance of compliance, 95, 110, 235, 242, 394 Asthma research, 77, 80, 167, 168-169, 191 Astrocytoma, 80 Atopic dermatitis, 77 Australian studies, 170, 172, 174, 186 AZT, 108 B Bartholome, William, 43 Bayley Scales of Infant Development, 125 Beaumont, William, 45 n.7 Beecher, Henry, 35, 39, 50, 248 Behavioral studies, 384-385 Belmont Report, 40-41, 43, 52-53, 93, 110, 255 Benefits of research, 1, 25-26, 58. See also Risk-benefit assessment collateral or indirect, 132 defined, 115-116, 395, 396 direct, 42, 132-133, 136, 154, 158, 204, 218, 396 ethical principles relating to, 40-44, 45 n.7, 47 expectations of, 150, 151, 164, 165, 167, 169, 170, 398 to other children, 115-116, 126-127, 149 n.2 peripheral, 149 n.2 potential, 115, 116, 133-134 prospective long-term studies, 39 Benzyl alcohol, 67 Bernard, Claude, 45 n.7 Best Pharmaceuticals for Children Act of 2002 , 2, 30, 68, 89, 106 n.3, 233, 400 Bilirubin, 69 Boston University, 48 Brazelton Neonatal Behavioral Assessment Scale, 125 Breast cancer, 171 Brokowski, Carolyn, 182

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Ethical Conduct of Clinical Research Involving Children C Caffeine, 70 California, 325, 340, 342, 344, 347, 354 Canada, 168, 173 Cancer research, 66, 71-72, 73, 77, 80, 81, 87, 88, 162, 170, 174, 175, 182, 189-190, 218 Cardiac disease, 67, 77, 87-88, 89 Center for Drug Evaluation Research, 55 Centers for Disease Control and Prevention, 161 Centers for Education and Research on Therapeutics, 90 Central Intelligence Agency, 95, 100, 321 Cerebral palsy, 77 Cherokee Nation, 116 Children. See also Assent cognitive development, 179-180 comprehension of research participation, 7, 183-185 defined, 63-64, 101, 154, 321 enrolled in clinical trials, 87 in foster care, 321, 322 n.2, 328 as interpreters for parents, 199 mortality rates, 80 neglected or abused, 154, 200, 328, 329, 335 outcome measures in, 76 pharmacokinetics in, 69, 70 Children’s Health Act of 2000 , 53, 54, 96, 100, 233, 400 Children’s Hospital Boston, 220-221 Children’s Hospital of Pittsburgh, 271 Children’s Oncology Group (COG), 71-72, 81, 88, 108, 261 Chloramphenicol, 27, 70 Chronic granulomatous disease, 80 Clinical investigation, definition, 33, 165 n.5 Clinical Investigation of Medicinal Products in the Pediatric Population, 111, 217 Clinical practice innovations, 32 “radically new” procedures, 32 Clinical research. See also Clinical trials; Pediatric drug research benefits of, 25-26 challenges, 59, 74-87 clinical care distinguished from, 34, 150 as complex, high-stakes enterprise, 35-36 context for, 59-62 definitions, 33-34, 395 experimental, 33, 396 importance of, 29 infrastructure, 83, 86-87, 92, 238 multidisciplinary, 86 organization and administration, 36 policies and procedures, 36 resources, 36 on stored biological specimens, 83 structures, 36 therapeutic vs. nontherapeutic, 33-34, 50, 331-337 unethical practices, 28, 331-332 Clinical trials. See also Multicenter trials; Pediatric drug research active treatment, 394 administering interventions and measurements, 78-79 behavioral considerations, 79 blinded, 151, 170, 395 children’s rules for, 188 control groups, 81, 108, 117, 139-142, 151, 396, 397 cooperative research groups, 71-72, 81, 87, 88, 91, 108 costs, 35, 83, 275 crossover studies, 81, 142 data on children’s participation, 87-88 designing and conducting, 2-3, 74-87, 91-92, 142-143 developmental considerations, 67, 71-72, 82 direct-benefit characterization, 34 disease-specific, 81 effect of participation on outcomes, 150 of emergency care, 87, 92, 155, 203 enrollment and retention of participants, 80, 87-88, 217-218, 220, 223-224 expertise of investigators in pediatrics, 3, 63, 78-79, 91-92, 93-94, 99, 136, 142-144, 244, 250 facility appropriateness, 78, 92, 136, 143 family-centered care, 84-85 with healthy children, 27, 50, 117 with ill children, 27, 160, 170, 197-198 long-term monitoring and evaluation, 82-83, 92, 275 minority participants, 87-88 outcome measures, 75-78

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Ethical Conduct of Clinical Research Involving Children perceptions and expectations of participants, 150, 151, 164, 165 n.5, 168, 170, 398 Phase 1, 72, 73, 133, 170, 397 Phase 2, 73, 397 Phase 3, 73, 397 placebo-controlled, 81, 108, 139-142, 155, 159, 164-165, 329-330, 398 progress reports, 99 prospective studies, 27 protocols, 398 quality-of-life interventions, 172 randomized controlled, 81, 159, 164-165, 168 recruitment practices, 217-218, 220, 223-224 registry, 88, 242 small study populations, 80-82, 91, 142 standard treatment, 398 suspension or termination, 194, 229, 234, 236 with wards of the state, 385-386 withdrawal from, 174, 183, 187-188, 190, 197, 215 Collins, Frances, 193 Colorado, 325, 340, 342, 344, 347, 354 Common Rule (45 C.F.R. Part 46, Subpart A), 320-321 agencies adopting, 54, 95 criteria for research approval, 3, 97, 99 defined, 395 exempted research, 53, 97, 99-100 expedited review, 53, 100, 117 historical evolution of, 52-53 informed consent, 53, 97 institutional assurances and responsibilities, 95, 96-97 institutional review boards, 97-99 minimal risk standard, 117, 121 vulnerable populations, 52 Compliance oversight accreditation perspective, 11, 21-22, 243-245 adverse event reporting, 105, 106-107, 231 assurance of compliance, 95, 110, 235, 242, 394 of child participants in research, 29, 55, 234-239 citations of noncompliance, 236 concerns about, 230-234 of conflicts of interest, 232 critical reports on, 231-234 data limitations and needs, 10-11, 230, 233, 234, 238-239, 240, 242, 243 determination letters, 29, 235-236, 396 by FDA, 56-57, 60 n.1, 105 n.3, 234, 236-238, 239 “for-cause” investigations, 232, 235 of foreign research, 56-57, 232-233 of human research, 230-234 monitoring, 37, 105, 106-107 “not-for-cause” evaluations, 232, 235 by OHRP, 232, 234, 235-236, 239, 241-242, 396 progress in, 29, 55 quality improvement perspective, 11, 235, 241-243 recommendations, 21-22, 238-239, 247-248 reporting requirements, 105, 106-107, 231 suspension or termination of research, 194, 229, 234, 236 voluntary actions by institutions and sponsors, 11, 238, 240-245 Comprehension of research participation. See also Assent; Consent process; Informed consent; Parental permission adolescents, 183-186 and assent, 7, 28, 42, 131-132, 181-193, 205-206 children, 7, 183-185 cognitive development and, 179-180, 205-206 competency standards, 185 in crisis situations, 7, 169-170 and decision making by parents, 166-178 experience with illness and, 131-132, 171, 189-190 format of presentation and, 181, 184 harms and benefits, 42, 163-164, 183-186 interpretation of terms, 165 n.5 parents, 159-178 purpose of research, 150, 164-165, 183-186, 398 readability of forms, 160-163, 195, 206 research needs, 208 rights of participants, 174, 183, 184, 187-189, 197 therapeutic misconception, 7, 150, 151, 164, 398

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Ethical Conduct of Clinical Research Involving Children Condition, defined, 128-129, 130 Conference on Social Responsibility in Pediatric Research, 48 Confidentiality assurances in consent process, 193 Certificate of, 395 ethical principles, 40 genetic studies and, 28 harm from violation of, 115, 116 for minors, 158, 187, 323, 327 regulations, 53, 388-390 translators and interpreters and, 199 Conflict of interest compliance oversight, 238 defined, 395 financial, 35 finders’ fees as, 223 nonfinancial, 35 physician recruitment of own patients as, 35-36, 223 regulations, 390-392 Connecticut, 340, 342, 344, 347, 355 Consent process. See also Assent; Informed consent; Parental permission accreditation standards, 244 for adolescents, 8, 9, 154, 156, 171-172, 192-194, 200-201, 204, 206, 207, 322 adverse events and, 107 advocates and independent research monitors, 154-155, 159, 202-203, 328-329 age appropriateness of, 7, 8, 156, 171-172, 173, 179-180, 183-185, 192-193, 205-207 assessment of participant’s understanding, 166 benefit and risk descriptions, 150-151, 154, 160, 163-164, 166, 184, 199-200 collaborative model of decision making, 173, 174-175, 209 community consultation and public disclosure, 155 continuous model, 171, 175, 177, 188-189, 192, 197-198 in crisis (acute-care) situations, 7, 169-170, 171, 175, 186, 192, 196, 197-198, 218 for emancipated and mature minors, 9, 157-158 for emergency care trials, 87, 155, 175, 203 family physician’s influence, 7, 152, 168, 173-175, 177, 213 family systems perspective, 172-173, 196, 203-205, 209 form design and content, 149-150, 153-154, 156, 160-163, 166, 181, 182, 184, 191, 193, 194, 198, 206, 207, 217, 222 for future use of stored tissue samples, 83 historical evolution of, 45-47, 48, 49-50 interpreters and translators, 177, 180, 198-199 investigator training for, 208 involvement of children in, 7-8, 40-41, 148, 149-151, 156-157, 171-173, 192, 205-207 IRB policies and practices, 7, 8, 140-141, 149-151, 156, 157, 158-159, 162-163, 193-195, 196, 201-203, 207 language and cultural considerations, 8, 175-176, 177, 180, 198-199, 206-207 litigation concerns and, 150, 152, 331-334 for multisite studies, 162-163, 194-195 outcome information presented in, 163-164 payment discussed in, 9, 215, 217, 222, 224-225 purpose of research presented in, 50, 84, 150-151, 159, 164-165, 182-186 quantitative information about outcomes, 163-164, 173 questions for parents to ask, 12, 177-178 recommended improvements in, 8, 18-21, 151, 166, 191, 195-209 regulatory requirements, 3, 4, 9, 48, 153-154, 400 research directions, 208-209 rights of participants explained, 174, 183, 184, 187-189, 197, 199 state laws and litigation, 201, 330-339 structure of, 8, 172-173, 196, 203-205, 209 treatment vs. research participation, 161, 164-165, 174

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Ethical Conduct of Clinical Research Involving Children type and amount of information, 157, 172-173, 174 undue influences on, 9, 173, 174, 213-214, 215, 216, 221 verbal presentation of information, 7-8, 156, 161, 166, 175, 181, 188-189, 194-195, 196, 207 views and results of, 168, 174, 175-176 waiver of parental permission, 9, 19-20, 154-155, 200-203 for wards of the state, 158-159, 200-201, 209 Consortium of Social Science Associations, 244 n.2 Control groups, 81, 108, 117, 139-142, 151, 396, 397 Cooperative research groups, 71-72, 81, 87, 88, 91, 108 Corticosteroids, 69, 71 Cosmetic surgery, 185 Council for International Organizations of Medical Sciences, 56-57, 127, 139, 217, 222, 256 Crossover studies, 81, 142 Cyclosporine, 27 Cystic Fibrosis Foundation, 88, 178, 218, 221, 262 Cystic fibrosis research, 75, 76, 77, 87, 108-109, 193, 271 Cytochrome P-450 1A2 , 70 D Data and safety monitoring boards composition of, 109 defined, 396 expertise in pediatrics, 37, 108, 252-253 federal regulations, 97, 107-110 independence of, 109, 110 responsibilities of, 108-109, 140 Data monitoring committees. See Data and safety monitoring boards Declaration of Helsinki, 33 n.4, 49-50, 57, 110, 111, 139 Delaware, 340, 342, 344, 347, 355, 364-365 Denver Developmental Screening Test II, 125 Developing countries, 57, 67 Diabetes research, 55, 65, 77, 87, 169, 184, 189, 190, 218, 271 Didanosine, 110 Diethylene glycol, 67 Disease, defined, 33 Disorder, defined, 128 District of Columbia, 340, 342, 344, 347 Dornase alpha (Pulmozyme), 76 Drug Amendments of 1962 , 400 Drug research. See also Pediatric drug research costs, 35 Drugs. See also specific drugs and classifications of drugs developmental issues, 60, 61, 65-72, 81 dosing schedules and errors, 68, 69-70 excipient safety, 67-68 extrapolation from adult studies, 2, 26-27, 43, 58, 60, 68-69, 71, 91 half-life, 69-70 labeling information for pediatric use, 60, 90-91 misbranding, 67 n.6 off-label use, 60-61, 67, 74, 397 Phase 1 trials , 397 E Economically disadvantaged persons, 10, 42-43, 46, 122, 213, 214, 224, 331-332, 333 Emancipated minors conditions for establishing, 323, 344-346 consent, 104, 157-158, 324 defined, 157, 323, 324, 325 n.10, 396 mature minors distinguished from, 325, 327-328 state laws, 323-324, 344-346 Engelhardt, Tristram, 43 Ethical principles adverse events, 46 AMA code, 45 n.7 Belmont Report, 40-41, 43, 52-53, 93, 110, 213 beneficence and nonmaleficence, 40-44, 45 n.7, 47 Declaration of Helsinki, 33 n.4, 49-50, 57, 139 education and training in, 268-270 foreseeable benefit of research and, 44 for future use of stored tissue samples, 83 historical evolution of, 44-53

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Ethical Conduct of Clinical Research Involving Children implementation, 85 informed consent and assent, 2, 40-41, 45-47, 48-49, 50, 84, 147-149, 192 justice, 41, 42-43, 57, 122, 129-130 nonbeneficial research and, 42, 43 Nuremberg Code, 46-47, 49 payment for participation, 41, 213-215 physician-patient relationship and, 44 placebo-controlled trials, 139-142 for research involving children, 7, 43, 51, 52-53, 93, 101, 183-185, 188 respect for persons (autonomy), 40-42 in review of protocols, 48-49 and trust, 25 UNESCO guidelines, 56 n.17 European Agency for the Evaluation of Medicinal Products, 111 European research, 175 Exempt research, 53, 99-100 Expedited review, 53, 99-100 F Federal agencies. See also individual agencies education and guidance for IRBs and investigators, 268-270 policy development, guidance, data collection, and research, 273-274 roles and responsibilities, 15-16, 18, 23, 267-274 under Common Rule, 54 n.1 Federal Food, Drug, and Cosmetic Act, 48, 67, 152, 230 Federal rules and regulations. See also Common Rule; Compliance oversight; Food and Drug Administration rules and policies; National Institutes of Health policies; Subpart D adverse event reporting, 105, 106-107 ambiguity in, 4, 94, 102-103, 106, 114, 230, 231, 232 applicable research, 230, 247 for assent, 3, 104, 151-153, 156-157, 182, 191, 204 assurance of compliance declaration, 97, 110, 394 for continuing review, 99 data and safety monitoring boards, 107-110 data monitoring committees, 105, 107-110 foreign research, 56-57, 110 historical evolution of, 52-57 minimal risk defined in, 115 for parental permission, 3, 152-155, 193 payment for participation, 215-217 Federation of American Societies of Experimental Biology, 244 n.2 Federation of Pediatric Organizations, 86 Fetal research, 52 Florida, 340, 342, 344, 348, 355, 364-365 Fluoxetine (Prozac), 60 Food and Drug Administration Modernization and Accountability Act of 1997 , 89, 400 Food and Drug Administration rules and policies adverse event reporting requirements, 106, 107 age categories, 63, 64, 65 compliance oversight, 60 n.1, 67 n.6, 88, 91, 105 n.3, 106-107, 108, 233, 234-235, 236-238 conformity with Subpart D, 5, 53, 95, 100, 400 data monitoring committees, 108 on foreign research, 110, 111, 233 Good Clinical Practices Program, 55, 68, 234-235 guidance on research involving children, 255 incentives for pediatric drug research, 2, 27, 90-91 for informed consent, 48, 94, 154, 400 on institutional review boards, 400 Investigational New Drug Application, 56, 111, 152 Office of Pediatric Therapeutics, 238 Office of Science and Health Coordination, 234-235 for parental permission, 9, 154, 155, 201-202, 203 payment guidelines for participants, 216, 217, 227 on pediatric drug trials, 2, 71, 73, 75-76, 90-91 on placebo-controlled trials, 139 n.8 protocols referred to Commissioner, 102, 116, 134

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Ethical Conduct of Clinical Research Involving Children recommended roles and responsibilities, 18, 23, 269 regulations, 3, 4, 9, 53, 54, 95-96, 100, 193, 230, 321, 400 review and monitoring program, 105, 106-107, 236-237 Forced expiratory volume at 1 sec (FEV1) , 76 G “Gasping syndrome,” 67 Gelsinger, Jesse, 55, 234 General Clinical Research Centers, 261 Genetic Alliance, 221 Genetic research, 75, 80, 116, 171, 182, 186, 193, 253 gene therapy trials, 28, 39, 55, 105, 109, 150, 234, 271 Georgia, 340, 342, 344, 348, 355 Germany, 46 Glantz, Leonard, 44 Glucuronyl transferase, 70 Gonorrhea, 45 Good Clinical Practices Program, 55, 68, 234-235 Good manufacturing practices, 68 Gorman, Richard, 90 “Gray baby syndrome,” 70 Guardians, 101, 154, 217, 321, 396 Guideline for Good Clinical Practice, 110-111 H Harbor-UCLA Medical Center, 271 Harm. See also Adverse events, risk defined, 114-115, 396 discomfort as, 115, 140 duration and magnitude considerations, 123, 126, 128, 134 identification of, 26 instances of, 67 prospective long-term studies, 39 unanticipated problems, 107 Hauerwas, Stanley, 43 Hawaii, 340, 342, 344, 348, 355 Health Insurance Portability and Accountability Act of 1996 , 94, 388-390 Hemophilia, 123 Hepatitis, 50 Hess, Alfred F., 46 Hexachlorophene, 69 Hippocrates, 40 HIV research and testing, 88, 108, 171-172, 194, 262, 264, 271 Hohmann, Elizabeth, 239 Human Genome Project, 28, 39 Human research participants protection program components or modules, 37 core functions, 37 defined, 396 ethical principles, 39-44 historical evolution of policies, 52 implementation challenges, 28, 29-30, 37-38 for multicenter trials, 37, 39 systems perspective, 36-39 Human subjects defined, 34, 396 Hyaline membrane disease, 27 I Ibuprofen, 167 Idaho, 340, 342, 344, 348, 356 Illinois, 340, 342, 344, 348, 356, 364-365 Immunosuppressive agents, 27 In vitro fertilization, 52 Indian Health Service, 116 Indiana, 325, 340, 342, 344, 348, 356 Infants defined, 63 experiments on orphans, 46 functioning and behavior, 125 instances of harm to, 67, 70 low-birth-weight, 82, 88 outcome measures in, 76 pharmacokinetics of drugs, 69-70 premature, 1, 26, 27, 58, 63, 67, 69, 75, 78, 80, 82, 87, 88 well-child examination components, 124 Informed consent. See also Assent; Comprehension of research participation; Consent process; Parental permission age of majority, 4, 94, 104, 154, 156, 325-326, 354-362 defined, 146, 395

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Ethical Conduct of Clinical Research Involving Children   by emancipated and mature minors, 157-158 ethical principles, 2, 40, 45-47, 48-49, 147-149 exempted research, 53, 97, 99-100 federal regulations, 53, 97, 151-153, 231 general conditions for, 51, 116, 148-149, 190 informational requirements for, 159 for long-term studies, 83 parental permission distinguished from, 148-149, 159, 198-200 for placebo-controlled trials, 139, 140-141 reading levels and readability of forms, 160-163 Institute of Medicine, 30, 233, 234, 243, 246, 251 Institutional review boards central review model, 265-266 community and family input to, 14-15, 254 composition, 35, 96, 97, 253-254 consent policies and practices, 7, 8, 143-144, 156, 157, 158, 193-195, 321, 327 continuing review by, 99, 107 database and information system, 266, 267 defined, 396-397 documentation of decisions and checklists, 55, 105, 134, 267, 242, 257-259, 260-261 expedited review, 53, 100, 117 foreign, 56 guidance on research with children, 15, 255-258, 268-270, 273 historical evolution of, 48-49, 51, 52 inspections of, 108 minimal risk interpretation, 118-121 monitoring adverse events, 107-108 multicenter protocol review, 255, 261-266 Native American, 116 payment policies, 216, 217-218, 219, 220-221, 224-225, 261 pediatric expertise on, 251-261 qualifications of members, 14, 22-23, 37, 76-77, 86, 97-99, 158, 244, 248, 251-255, 321 recommendations, 14, 15, 18, 22-23, 138, 253, 258, 266 referral of protocols to the DHHS Secretary or FDA Commissioner, 102, 103, 116, 134, 137 n.6, 270-273 regulatory framework, 96-97, 97-99, 101, 321, 400 roles and responsibilities, 13-15, 28, 49, 51, 53, 96-97, 105 n.3, 106, 108-109, 138, 232, 247, 251-267 sharing information about decisions, 55, 105, 134, 267, 274-275 supplemental policies and guidance, 258, 261 variability in decisions, 262-265 waiver of parental permission, 19, 84 written basis for judgments, 6, 134 Intelligence tests, 125 International Conference on Harmonisation, 33 n.4, 56, 63, 71, 111, 139, 156-157, 217, 396, 397 International Covenant on Civil and Political Rights, 49 n.12 International Ethical Guidelines for Biomedical Research Involving Human Subjects, 111 International research, regulation of, 56-57, 110, 232-233 Interventions, defined, 34 Intraocular lens replacement, 61 Investigators and research teams child life specialists and child psychologists, 79 consent policies and practices, 20, 84, 193-195 cultural sensitivity, 84 expertise in pediatrics, 3, 20, 63, 78-79, 91-92, 93-94, 99, 136, 142-144, 244, 250 inspections of, 108 minimal risk interpretations by, 118-121 payments to, 222-223, 227-228 progress reports, 99 recommendations, 19, 250 roles and responsibilities, 12-13, 35, 84, 99, 142-143, 248-251 training and retention of, 86-87, 250 Iowa, 340, 342, 344, 348, 356 Ivy, Andrew, 46, 47 n.10

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Ethical Conduct of Clinical Research Involving Children J Jenner, Edward, 45 Jewish Chronic Disease Hospital Study, 331-332 Johns Hopkins University, 332 Joint Commission on the Accreditation of Healthcare Organizations, 244 Jonsen, Albert, 53 n.14 K Kansas, 340, 342, 344, 348, 356 Kennedy Krieger Institute, 331-332 Kentucky, 340, 342, 344, 349, 356-357 Kernicterus, 69 Kidney disease, 92 Koski, Greg, 229 L Lamivudine, 110 Lasagna, Louis, 47 Lead abatement studies, 330-331 Legally authorized representative, defined, 101 Legislation. See also Regulatory framework for protection; specific statutes incentives for pediatric research, 89-90 Leukemia, 26, 66, 75, 80, 82, 87, 88, 106, 169, 184 Lilly, Joseph, 169 Lilly, Maureen, 58 Lippincott, Sarah, 191-192 Long-term studies implementation, 83 importance, 82 Louisiana, 340, 342, 344, 349, 357, 364-367 M Maine, 325, 340, 342, 344, 349, 357, 366-367 Maryland, 328, 331-334, 339, 340, 342, 345, 349, 357 Massachusetts, 336, 340, 342, 345, 349, 357 Maternal and Child Health Bureau, 89 Mature minors abortion law, 336 consent to research, 104, 158, 203, 204, 206, 323 consent to treatment, 336-337, 347-352 defined, 325, 397 emancipated minors distinguished from, 325, 327-328 state laws, 324-325, 336-337, 347-352 status events for consenting to health care, 347-352 McCormick, Richard, 43 Measles, 1, 26, 45 Medical Device User Fee and Modernization Act of 2002 , 60 n.1 Medical experiment, 165 n.5 Medical research, 165 n.5 Medical study, 165 n.5 Mentally ill, institutionalized persons, 42-43, 50, 51 n.13, 334-336 Methylphenidate (Ritalin), 60 Michigan, 340, 342, 345, 349, 357 Midazolam hydrochloride (Versed), 89 Minimal risk “daily life” reference, 5, 118, 121, 126 defining, 5, 115, 117-126, 397 developmental status or age considerations, 122, 124, 126 discomfort as, 115 ethical principles, 47 exemption or expedited review, 53 for healthy children, 5, 117, 120, 121-125, 126 for ill children, 120, 122-123 investigator and IRM interpretation, 118, 120-121 moral and social implications, 5, 120-121 and no benefit to participant, 84, 103, 127 procedures categorized as, 123, 134-136 psychological tests, 125 recommended interpretation, 5-6, 126 relativistic interpretation, 5, 121-122, 126, 127 routine examination standard, 4, 124-125 socially allowable risks, 123 Minnesota, 340, 342, 345, 350, 357 Minor increase over minimal risk standard benefit standard, 6, 115-116, 130, 328-329 commensurate procedure criterion, 128, 131-132, 395

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Ethical Conduct of Clinical Research Involving Children defining, 118, 120, 126-128, 397 disorder or condition criterion, 6, 128-131, 395 recommendations, 130-131 research-only procedures, 137 Minorities, 175 Mississippi, 104, 340, 342, 345, 350, 358 Missouri, 340, 342, 345, 350, 358 Montana, 340, 342, 345, 350, 358 Mothers of Asthmatics, 221 Multicenter trials consent process, 162-163, 194-195 defined, 397 enrollment and retention of participants, 84 in foreign countries, 110 implementation of protective policies, 28, 37, 39 need for, 92 protocol review, 261-266 reporting adverse events, 107 risk categorization in, 120 size of study populations, 81 state regulation of, 4-5 variable review of, 261-266 Mumps, 1 N National Academy of Sciences, 25 National Association of State Universities and Land Grant Colleges, 244 n.2 National Bioethics Advisory Commission (NBAC), 32-33, 34, 35, 56, 83 n.8, 113, 117, 136-137, 223, 232-233, 248 National Cancer Institute, 87, 108, 162, 265 National Center for Health Statistics (NCHS), 63, 64 National Commission for Quality Assurance, 244 National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 6, 33 n.4, 40, 43, 51 n.13, 52, 53, 93, 101, 125, 126, 127, 129, 131-132, 134, 136, 138, 139, 154, 156, 200, 201, 268-269, 400 Belmont Report, 40-41, 43, 52-53, 93, 110, 255 Research Involving Children, 52-53, 255 National Conference of State Legislators, 338 National Governors Association, 338 National Health Council, 244 n.2 National Human Research Protections Advisory Committee (NHRPAC), 122, 123, 127, 129, 131, 135, 269 National Institute of Allergy and Infectious Diseases, 88 National Institute of Child Health and Human Development (NICHD), 88, 89 National Institutes of Health policies, 178, 234 age categories, 64 Certificate of Confidentiality, 395 Clinical Center, 47-48, 52, 222 clinical research curriculum grants, 86 historical evolution of, 47-48, 52 incentives for research, 2, 27, 52, 91-92 IRB database and information system, 266, 267, 275 for monitoring data and safety, 105, 108 notification of institution’s noncompliance, 236 parental permission, 155 on payment for participation, 219-220, 222, 227 prospective studies of immunosuppressive agents, 27 recommended roles and responsibilities, 23, 269 regulations applicable to, 95, 97 National Research Act of 1974 , 52, 400 National Research Council, 30 Native Americans, IRBs, 116 Navaho Nation, 116 Nebraska, 104, 340, 342, 345, 350, 358 Nebulized albuterol, 60 Nelson, Robert M., 211 Nelson Textbook of Pediatrics, 63, 64, 65 Neonatal Research Network, 88 Neonates, 63, 69, 70, 124, 168, 175. See also Infants Netherlands, 167 Nevada, 340, 342, 345, 350, 358 New England Medical Center Hospital, 271 New Hampshire, 341, 342, 345, 350, 358, 366-367 New Jersey, 341, 342, 345, 350, 358-359, 366-367

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Ethical Conduct of Clinical Research Involving Children New Mexico, 341, 342, 345, 351, 359, 368-369 New York, 334-336, 339, 341, 342, 345, 351, 359 New Zealand studies, 167-168 North Carolina, 341, 342, 345, 351, 359 North Dakota, 341, 342, 345, 351, 359, 368-369 Nuremberg Code, 46-47, 49, 152 Nutrition research, 184 O Obesity, 77, 80 Office for Human Research Protections, 53 n.15, 136 central IRB review model, 265-266 compliance oversight by, 55, 99, 216, 229, 232, 233, 234, 235-236, 239, 396 determination letter, 216, 396 guidance on research involving children, 255 payment guidelines, 215-216 quality improvement initiative, 235, 241-242 recommended roles and responsibilities, 6, 18, 23, 136, 155, 202, 203, 239, 269, 270, 272 Office for Protection from Research Risks, 55 Office of Management and Budget, 239, 241 Office of Public Health and Transfer, 55 Ohio, 341, 342, 345, 351, 360 Oklahoma, 341, 342, 345, 351, 360, 368-369 Oregon, 325, 341, 342, 346, 351, 360 Organ transplants, 27 Otitis media, 80 Outcome measures age-appropriate, 75-77 consent and quantitative information about, 163-164 death, 75 defining, 75-78 developmental appropriateness, 76-77 normative data, 78 pain scales, 77 physical or cognitive functioning, 76-77 quality-of-life, 77 surrogate measures, 75-76 survival after diagnosis and disease-free survival, 75 Oversight of regulations. See Compliance oversight P Pain assessment and management, 77, 79 Parental permission. See also Assent; Consent process; Informed consent compensation and, 331 comprehension level and, 7, 42, 131-132, 159-178, 198-200 conditions/disorders not requiring permission for treatment, 354-362 crisis-driven decision making, 169-170, 171 decision-making process, 166-178 defined, 101, 146, 397 ethical principles, 148 exceptions to requirements for, 324 expectations of benefit and, 151, 164-165, 167, 169-171, 199-200 experience of illness and, 171 family physician’s influence, 7, 168 federal regulations, 103-104, 152-155 forms, 193 by guardians, 49-50, 146, 154, 396 informational requirements for, 159-160 informed, 198-200 informed consent distinguished from, 148-149, 159 investigator’s undue influence on, 173, 174 legal requirements for, 3, 151-155, 331-337 limits of authority, 335 motivation for decisions, 167-169 process, 149-151, 175-176 reading levels and readability of forms, 160-163 research on decision making, 166-178 risk-benefit standards, 331-337 views and results of consent process, 168, 174, 175-176 waiver of, 4, 9, 19-20, 51, 84, 94, 97, 104, 154-155, 193, 194, 200-203, 321, 335

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Ethical Conduct of Clinical Research Involving Children Parents compensation for time and inconvenience, 10, 212, 214, 217, 219, 220, 221, 227, 228, 395 defined, 101, 154, 397 incompetent, 154 influence of children, 187, 190-191, 204-205 participation in clinical studies, 34 questions to ask during consent process, 12, 177-178 reimbursement for expenses, 10, 212, 213, 214, 217, 218, 219, 220, 225-226, 398 responsibilities of, 160 termination of rights, 329 Participants, defined, 397 Partnership for Human Research Protection, Inc., 244 Pattee, Suzanne, 178 Payment for participation acceptable types of, 10, 225-227 to adolescents, 10, 213, 218-219, 227 amounts paid, 217, 218, 219 bonuses for completion of study, 217, 224 and child’s assent, 189, 211 compensation for time and inconvenience, 10, 212, 214, 217, 219, 220, 221, 227, 228, 395 ethical concerns, 9, 41, 211, 213-215, 220 federal regulations and policies, 215-217, 220, 227 to guardians, 217 incentive payments, 189, 212, 213, 214-215, 216, 221, 227-228, 396 for injuries related to research, 221-222, 227 IRB policies and practices, 9, 216, 217-218, 219, 220-221, 223, 224-225 nonfinancial alternatives, 10, 214, 228 OHRP guidelines, 215-216 and parental permission, 331 to physicians’ for finders’ fees, 222-223, 227-228 professional organizations’ positions on, 221 recommendations for improving, 9-10, 21, 223-228 recruitment advertising, 217-218, 220, 223-224 reimbursement for expenses, 10, 212, 213, 214, 217, 218, 219, 220, 225-226, 398 research on use of, 217-220, 227 and risk-benefit assessment, 132, 216, 331 risk-related, 10, 216, 218, 219-220, 221, 226-227 token payments or gifts, 212-213, 215 types of, 212-213, 221 undue influence of, 9, 213, 214, 221 waiver of treatment costs as, 221 written policies on, 9, 222, 224-225 Pediatric AIDS Clinical Trials Group, 88 Pediatric drug research. See also Clinical research; Clinical trials with adolescents, 7, 64-66 adverse effects by developmental stage, 67, 71-72, 82 age-appropriate formulations, 26-27, 61, 66, 67-68, 73 with children, 63-64, 69, 76, 78, 79 commercial value of, 61-62, 89 costs of, 61 data monitoring committees, 108 direct benefits of, 133 disclosure of findings, 27 n.1, 106, 250 efficacy trials, 73, 133 ethical and regulatory standards, 60 n.1, 62, 63, 85 incentives for, 30, 59, 89-92 with infants, 63, 67, 69, 70, 76, 78, 79 information gaps, 26-27 labeling for pediatric doses, 89 long-term follow-up and surveillance, 71-72, 75, 76, 82-83, 106, 275 normative data, 75, 76, 78 patent protection, 89 payment for participation, 217 rationale for, 66-72 reporting adverse events, 106-107 pharmacodynamics, 66, 71, 72-73 pharmacokinetic studies, 26-27, 63, 66, 68-70, 72, 73, 133 process for, 72-74 for unique diseases, 67, 72, 73, 78 waiver of labeling requirements, 90 Pediatric Emergency Care Applied Research Network, 155 Pediatric Pharmacology Research Network, 88

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Ethical Conduct of Clinical Research Involving Children Pediatric Research Equity Act of 2003, 90, 400 PedsQL 4.0 instrument, 77 Pellegrino, Henry, 248 Pennsylvania, 341, 342, 346, 351, 360 Percival, Thomas, 45 n.7 Pertussis, 45, 168 Pharmacodynamics, 71, 397 Pharmacokinetics, 68-70, 397 Phenolbarbitol, 71 Phenylketonuria, 58 Phenytoin, 69 Placebo-controlled trials, 81, 108, 139-142, 155, 159, 164-165, 329-330, 398 Polio, 1, 26 Polycystic ovary syndrome, 65 Pregnant women, 52 President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, 53-54 Prisoners, 42-43, 52, 159, 231, 321, 328 Privacy issues, 115, 158, 187, 205, 323, 327, 339 Professional societies. See also individual organizations recommended role of, 250-251 Protection of Pupil Rights Amendment, 321 Prussia, 45 Pseudomonas aeruginosa infection, 109 Psoriasis research, 217 Public Citizen, Health Research Group, 221 Public Responsibility in Medicine and Research, 244 n.2 Public review and comment process, 55 Pulmonary hypertension, 89 Q Quality improvement government initiative, 39, 55, 241-243 projects as research, 32 R Radiation experiments, 48, 50 Radiation therapy, 26, 59, 82 Ramsey, Paul, 43 REACH (Reaching for Excellence in Adolescent Care and Health), 262 Recombinant DNA Advisory Committee, 269 Recommendations assent and permission process, 8, 18-21, 151, 166, 191, 195-209 compliance oversight, 10-11, 21-22, 238-239, 247-248 data collection, 10-11, 23, 238-239, 247-248, 273-274 federal agency responsibilities, 23, 273-274 institutional review boards, 14, 15, 18, 22-23, 138, 253, 258, 266 payment policies, 9-10, 21, 223-228 risk-benefit assessments, 5-6, 17-18, 126, 127-129, 130-131, 134-136, 138 Recruitment of participants, 217-218, 220, 223-224 Regulatory framework for protection. See also Compliance oversight; Federal rules and regulations; State regulatory framework; specific statutes conflict of interest, 390-392 historical evolution of policies, 45-54, 151-153, 231 importance of, 3, 29 international efforts to harmonise, 56-57 privacy of subjects, 388-390 Research. See also Clinical research; Pediatric drug research definitions, 31-33, 114 quality improvement projects distinguished, 32 Research Involving Children, 52-53, 255 Retinoblastoma, 80 Retinopathy of prematurity, 1, 26 Rhode Island, 341, 342, 346, 351, 360-361, 368-369 Rhode Island Hospital, 271 Risk. See also Minimal risk defined, 114, 398 to others, 116 procedures categorized by, 5-6, 123, 134-136 reasonableness of, 138-142 Risk-benefit assessment algorithm, 117, 119 basic concepts, 114-116 clinical equipoise criterion, 138-142

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Ethical Conduct of Clinical Research Involving Children commensurate procedure criterion, 6-7, 128, 130, 131-132, 395 by components vs. whole protocol, 136-138 and consent issues, 131, 140-141, 154, 163-164, 331-337 correlates of health and disease and, 129-130 developmental status or age considerations, 6, 122, 124, 126, 128 direct benefit standard, 42, 132-133, 138 disorder or condition criterion, 6, 126, 128-131, 133, 136, 395 environmental considerations, 133 ethnic, cultural, and religious considerations, 116 foreseeable benefit to others, 126-127 government guidance, 134-136 justice considerations, 122, 129-130, 131 minimal risk standard, 5, 6, 102-103, 117-126, 136 minimization of risk from procedures, 134-136, 142-144 minor increase over minimal risk standard, 102-103, 126-128, 136, 137, 138, 140 no benefit to participant, 84, 103, 127, 130-131, 132-134, 137, 138, 331-337 payment for participation and, 132, 216, 331 placebo-control trials, 139-142 presentation of information in consent forms, 163-164 privacy considerations, 28 prospective long-term studies, 39 recommendations, 5-6, 17-18, 126, 127-129, 130-131, 134-136, 138 regulatory framework, 5, 101-103 required determinations, 117, 118 subjectivity of, 118, 120, 265 vital importance standard, 6, 130, 133-134 Roche, Ellen, 234 S Sagan, Leonard, 44 Schizophrenia, 27 Secretary’s Advisory Committee on Human Research Protections (SACHRP), 6, 18, 122 n.1, 134, 135, 136, 272, 273 Shirkey, Harry, 59 Simone, Joseph V., 66 Sleep research, 55, 271 Smallpox research, 45, 46, 55, 116, 133, 271 Social Security Administration, 95, 100, 321 Society for Adolescent Medicine, 201, 202, 203, 251 Society for Pediatric Research, 221, 251, 254, 270 South Carolina, 325, 341, 342, 346, 352, 361, 368-369 South Dakota, 341, 342, 346, 352, 361, 368-369 Sponsors of research financial rewards, 35 roles and responsibilities, 274-275 Stanford-Binet Intelligence Scale, 125 State regulatory framework age of consent for medical care, 4, 94, 104, 156, 201, 322-323, 325-326, 354-362 age of majority, 4, 94, 322-323, 342-343 case law examples, 328, 330-337 education-related research in school settings, 340-341, 344-346 emancipated minors, 323-324 illustrations of state laws, 331-337 mature minor provisions, 324-325, 347-352 recommendations, 4-5 research-specific legislation, 326-328 research-specific regulations, 328-330 uniform guidelines and national discussion, 337-339 wards of the state, 328-330, 364-375, 384-387 Subpart A. See Common Rule Subpart D age of majority, 322 agencies adopting, 95, 96, 100, 232, 321 ambiguities in, 232 categories of approvable research, 3, 4, 102-103, 117 consent to participate in research, 3, 103-104, 322 defined, 398

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Ethical Conduct of Clinical Research Involving Children definitions, 101 historical evolution of, 53 minimal risk standard, 117, 121 risk-benefit assessment, 101-103, 133-134 Sudden infant death syndrome, 75, 167-168 Sulfanilamide, 67 Sulfonamides, 67, 69 Surfactant therapy, 26, 27 Syphilis, 45 T Tennessee, 336-337, 341, 342, 346, 352, 361, 368-373 Tetracyclines, 71 Texas, 341, 342, 346, 352, 361 Theophylline, 70 Therapeutics Development Network (TDN), 88, 218, 262 Therapeutic misconception, 7, 150 Tobramycin solution for inhalation (TOBI), 76, 108-109 Toulmin, Stephen, 43 Tuberculosis studies, 46, 195 Tuskegee Syphilis Study, 52, 331 Typanocentesis, 120 U United Nations, 49 n.12 Education, Social and Cultural Organization, 56 n.17 University of California at Los Angeles, 220, 271 University of Maryland, 332 University of North Carolina, 271 University of Pennsylvania, 28, 55 University of Rochester Medical Center, 321 n.1 University of Washington, 222, 271 U.S. Department of Education, 54, 95, 100, 321 U.S. Department of Health and Human Services policies. See also Food and Drug Administration adverse event reporting requirements, 106, 107 age categories, 64 compliance oversight, 231-232, 233 criticisms of, 55, 94 on foreign research, 110-111 funding allocations, 90 historical evolution of, 51, 52-53, 54 on investigator qualifications, 99 on payment of participants, 214, 220, 223, 227 protocols referred to the Secretary, 103, 116, 134, 137, 270-273 public review and comment process, 55 regulations on protection of human subjects, 2, 3, 4, 9, 52-53, 94, 95, 96, 100, 102-103, 106, 153, 155, 193, 200, 230, 321, 400-401 U.S. Department of Health, Education and Welfare, 51, 52, 54 U.S. General Accounting Office, 88, 231-232 U.S. Public Health Service grants, 49, 153 U.S. Surgeon General, policy statements, 48-49, 51, 152-153 Utah, 341, 343, 346, 352, 361, 372-373 V Vaccine research, 26, 27, 45, 50, 55, 116, 133, 161, 168, 183, 271 Vaughn, Andrell, 146 Vermont, 341, 343, 346, 352, 361 Veterans Administration, 222 Virginia, 341, 343, 346, 352, 361 Vulnerable groups consent laws, 51 n.13, 320, 322, 329-330, 331-337 economically disadvantaged persons, 42-43, 46, 122, 331-332, 333, 337 mentally ill, institutionalized persons, 42-43, 50, 51 n.13, 334-336, 337 prisoners, 42-43, 52, 159, 231, 321, 328 underuse and overuse of, 42-43 W Wards of the state consent laws, 104, 158-159, 200, 321, 328-330, 338, 364-375 defined, 101, 398 experimental research on, 50, 338 protocol scenario, 384-387 Washington State, 167, 341, 343, 346, 352, 362, 374-375

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Ethical Conduct of Clinical Research Involving Children Wechsler Intelligence Scale for Children, 125 Wechsler Preschool and Primary Scale of Intelligence, 125 West Virginia, 341, 343, 346, 352, 362 Willowbrook State School, 50, 332 n.15 Wisconsin, 341, 343, 346, 352, 362, 374-375 Women’s Health Initiative, 43 World Health Organization, 56 n.17 World Medical Association, 49, 110, 139 Worsfold, Victor, 43 Wyoming, 341, 343, 346, 352, 362 Y Yasui, Lise, 196