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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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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
Representative terms from entire chapter:
ethical principles
