A
Abacavir sulfate, 48
Abatacept, 55, 300, 301, 325t, 359t
Abobotulinumtoxin A, 325t, 359t
Absorption, drug, 45
Acetaminophen, 154b
Active moiety, 74, 76, 179
Adalimumab, 120b, 132b, 151, 201b, 294–295, 300–301, 307, 326t, 360t
Adolescents
developmental pharmacology, 47
in pediatric age range, 47
Adults, pediatric drug use based on studies with
analysis of clinical reviews of, 119, 120b
extrapolation of safety in, 123–124
risks in, 4, 30, 273
See also Alternative endpoints; Extrapolation of efficacy
Adverse Event Reporting System, 68, 272
Adverse events
data sources, 11–12
definition, 11, 39, 115–117
during clinical trials, 114–115
frequency and types of, in pediatric studies, 117–123
long-term concerns, 61
off-label prescribing as cause of, 272
postmarket surveillance, 68–70
reporting requirements, 117
research objectives, 5
suggestions for clinical assessment format, 12, 139
Agalsidase beta, 326t, 360t
Agency for Healthcare Research and Quality, 125
Albumin (human), 190, 327t, 372t
Albuterol sulfate, 57, 133
Alefacept, 327t, 360t
Alemtuzumab, 327t, 360t
Alendronate, 121, 132b
Alglucosidase alfa, 212, 213, 327–328t, 361t
Almotriptan, 103, 121, 184b
Alpha1-proteinase inhibitor, 222b, 224b, 328–329t, 372–373t
Alternative endpoints
composite endpoints as, 53–54
definition, 12, 39, 128–129
study goals, 5, 12
suggestions for reporting on use of, in studies, 12, 140
surrogate endpoints as, 53, 129–130
use of, in pediatric studies, 12, 52–53, 129, 130–133, 132b, 194
American Academy of Pediatrics, 30, 43–44, 274
Amlodipine besylate, 74
Amlodipine maleate, 74
Ampicillin, 164–165
Anakinra, 329t, 361t
Animal studies, 55
Antihemophilic factor, 124, 147, 329–330t, 373t
Anti-infective agents, 141, 273t, 279
Antithrombin, 222–223b, 331t, 373t
Antithymocyte globulin, 217, 331t, 374t
Approval letters, 188–189, 190
for biologics, 218
Aripiprazole, 61, 120b, 127, 132b, 200–201b, 202b
Arrhythmias, 56–57, 122, 149, 199b
Artemether/lumefantrine, 213–214
Arthritis, juvenile rheumatoid. See Rheumatoid arthritis
Assent to research participation, 94
Association of Am. Physicians & Surgeons, Inc. v. FDA, 33
Asthma, 21, 23b, 48, 51, 120b, 121, 132–133, 198b, 202b
Atopic dermatitis, 302–303
Attention deficit hyperactivity disorder, 48, 69, 122n, 125, 199b
Autism, 151n
Autologous cultured chondrocytes, 331t, 374t
Azithromycin, 164
B
Basilixmab, 332t, 361t
Becaplermin, 224b, 226, 227, 332t, 361t
Belmont Report, 30–31
Benzyl alcohol, 30
Besifloxacin ophthalmic, 158–159
Best Pharmaceuticals for Children Act
age range covered by, 4–5
biologics coverage added, 3, 7–8, 16, 27, 34, 207
biologics with possible promise for pediatric study, 226
clinical reviews, 112–114
cost-benefit analysis, 109
data sources for analysis of, 5–6, 112
effects on clinical practice, 25
ethical implementation, 89, 99–108
extrapolation studies under, 137–139, 137t, 138t
FDA administrative structure for, 83–84
incentive program, 62, 70–74
labeling changes supported by studies under, 14, 178, 194, 195t
neonatal assessments under, 14, 141, 148, 149–151, 165–167
NIH role, 8–9, 14, 35, 76–77, 96, 163–165, 166–167, 188, 226–227
objectives, 1, 8–9, 19, 111, 271
one-year safety reviews, 125–126
outcomes to date, in pharmaceutical safety and effectiveness, 2–3, 6–8, 26–27
Pediatric Research Equity Act and, 34, 81
potential of requests to generate useful information, 183–187, 186b
proposal for permanent reauthorization, 86–87
public access to studies conducted under, 3, 11, 84–86, 100–102, 109, 112, 272
reauthorizations, 3, 7, 9, 27, 87
requests for studies of off-patent products, 76–77
safeguards for pediatric research, 10
salient issues in analysis of, 1, 5, 24, 28, 261–262
scope and outcomes of studies under, 2, 14–16, 22b, 23b, 34, 74–76, 177–183, 178f, 182f, 203
sources of requests, 182, 226
strategies for improving, 3, 166–167
suggestions for neonatal assessments under, 14, 166–167
types of labeling changes made under, 197–203
Betamethasone, 164
Better Pharmaceutical for Children, 32
Bevacizumab, 309, 332t, 362t
Biologics
access to application and review data, 215
approval letters, 218
biosimilarity and interchangeability, 208–209
clinical pharmacology, 292–293
clinical trials registry, 219–220, 359–379t
current pediatric labeling, 3, 16–17, 27, 217–218, 220–221, 228
data sources for analysis of pediatric research, 6, 178, 215–220, 263, 321–324
definition, 7n, 64–65, 208n, 210, 286
developmental pharmacology, 313
extension of BPCA to, 3, 16, 27, 34, 63, 207, 208–215
future prospects, 17, 228–229
historical and technical evolution, 285–286
labeling information on FDA-approved products, 220–221, 325–358t
labeling requirements, 67–68
market exclusivity protections for, 71–73, 207, 209, 210, 211, 228
mechanism of action, 290
neonate studies, 146–147
Orphan Drug Act and, 34, 78, 212–213, 228
outcomes to date of legislative requirements for research on, 3, 7–8, 27
plasma-derived, 287–288, 288t, 293, 294
PREA requirements for, 7, 16, 33, 78, 207, 214–215, 222–223b
priority review vouchers, 213–214
products not tested for pediatric use, 5, 215, 222–226, 224–225b
products studied with children, 7–8, 27, 220–221, 221t, 359–379t
products with possible promise for pediatric study, 226–227, 228
recombinant-derived, 288–290, 291–292t
safety concerns, 294–295
salient issues in pediatric medicine, 1, 2, 5, 24–25, 207–208, 262
sources of, 286–287
structure, 287, 287f
suggestions for research, 3, 16, 229
supplemental license applications, 209
therapeutic applications, 296–313
types of, 287–290
See also Biologics License Application; Center for Biologics Evaluation and Research; Vaccines
Biologics Control Act, 29, 285
Biologics License Application, 9, 65–66, 114, 151, 188, 209
priority review, 213
supplemental, 209
Biologics Price Competition and Innovation Act, 2, 5, 24, 63, 207, 208–211, 214–215, 228–229, 262
Biosimilar products, 208–209
Biospecimen sampling, 54–55
Bipolar disorder, 127
Bivalirudin, 174t, 180
Botulism immune globulin, 41, 333t, 374t
Bronchopulmonary dysplasia, 119, 129, 149
Buspirone hydrochloride, 132b, 138, 202b
C
C1 esterase inhibitor, 333t, 374t
Caffeine citrate, 144–145
California Department of Health Services, 41
Canakinumab, 334t, 363t
Cancer, 308–310, 312–313
Candesartan, 201b
Candidiasis, 273
Caspofungin, 170t
Ceftaroline fosamil, 152
Ceftriaxone, 143
Center for Biologics Evaluation and Research, 29–30, 83, 84, 97, 112, 114, 180, 193, 216, 286
suggestions for, 12, 139
Center for Devices and Radiological Health, 97
Center for Drug Evaluation and Research, 12, 83, 84, 97, 112–114, 115, 128, 130, 180, 193, 286
Certolizumab pegol, 334t, 363t
Cetuximab, 309, 334t, 363t
Children’s Health Act, 93, 309
Children’s Oncology Group, 59, 196–197
Chloramphenicol, 43–44, 90, 141
Ciprofloxacin, 158, 174t
Cisapride, 101
Clinical and Translational Science Awards, 59
Clinical practice, 25, 39
clinician awareness of labeling changes, 274–275
sources of prescribing information, 276–281, 277–278t, 281t, 282
Clinical reviews by FDA
analysis of efficacy assessments in, 131–133
analysis of safety assessments in, 11, 117–123
audience, 113–114
as data source, 112–113
definition, 112–113
description of endpoints in, 12, 131–133, 194
description of research design and integrity in, 10, 100, 102–103, 109
discussion of developmental variability, 194
effects on labeling, 118, 119
efficacy review template, 128, 129b
justification for use of extrapolation of efficacy in, 13, 134–136
public access to, 13, 109, 112
quality of, 112, 114, 139, 193–194
redacted material, 10–11, 100, 102, 109–110, 118, 119, 158, 193
safety review template, 12, 115, 116b, 139, 193
scope of, 113
sources of, 112
suggestions for, 10, 12, 139
template for reviews, 113b
Clinical trials
abandoned, 101
conducted outside the United States, 92–93
data integrity, 91
database, 219n
definition, 37–38
drug delivery documentation, 51
ethical issues in, 10
limits of short-term studies, 61
for pediatric populations, 55–56
pharmacogenetic considerations in, 48–49
protection of research participants, 90–96
registry, 219–220, 359–379t
safety assessment and monitoring in, 114–115, 117
support infrastructure for pediatric research, 58–60
trial design, 56–58
types of, 38b
See also ClinicalTrials.gov
ClinicalTrials.gov, 11, 85, 102, 110, 219, 323
Clopidogrel, 58, 149, 154b
Coagulation factor IX, 335t, 375t
Coagulation factor VIIa, 335t, 374t
Collagenase clostridium histolyticum, 225b, 335t, 363t
Composite endpoints, 53–54
Confidentiality and privacy
protections for research subjects, 90
redactions in clinical reviews to protect, 193
Conflict of interest, 90, 102
Conjunctivitis, 101, 147, 153, 157–159
Corticosteroids, 48
Cost-benefit analysis of BPCA and PREA, 109
Creating Hope Act, 213
Crohn’s disease, 305–308
Crotalidae polyvalent immune Fab, 217, 336t, 375t
Cystic fibrosis, 35
Cystic Fibrosis Foundation, 60
Cystic Fibrosis Therapeutic Development Network, 60
Cytochrome enzymes, 45, 46
Cytomegalovirus, 103
D
Daclizumab, 336t, 364t
Darbepoetin, 337t, 364t
Darunavir, 150
Data monitoring committee, 114–115
Declaration of Helsinki, 92, 104
Denileukin diftitox, 337t, 364t
Denosumab, 337t, 364t
Department of Health and Human Services, 90, 93
Desflurane, 120b, 128, 200b, 203
Developmental pharmacology
of biologics, 313
consideration of, in FDA reviews, 194
implications for drug formulation and delivery, 49–52
implications for pediatric research design, 54–58
long-term use of drugs, 61
pharmacogenetic factors, 48–49
research support infrastructure for consideration of, 58–60
in selection of endpoint measures, 52–54
significance of, 44–48, 49
Dextromethorphan hydrobromide, 133
Diabetes, 22b, 310–312, 313
Didanosine, 156, 173t
Diethylene glycol, 29
Difluprednate ophthalmic solution, 147n
Digoxin immune Fab, 338t, 375t
Diphtheria antitoxin, 29
Division of Scientific Investigations, 98, 102
Dosing
clinician access to new information on, 274
developmental pharmacology, 46
extrapolation of pediatric dose from adult studies, 4, 273, 273t
label guidelines for off-label pediatric use, 15–16, 204
sources of prescribing information for pediatric clinicians, 276–281, 277–278t, 281t, 282
subtherapeutic, 96
suggestions for pediatric research, 15, 203
See also Developmental pharmacology
Drotrecogin alfa, 338t
Drug Facts and Comparisons, 279
Drugs, definition of, 64
Drugs@FDA, 100, 274
E
Ecallantide, 339t, 364t
Eculizumab, 339t
Effectiveness of medical intervention, 39
substantial evidence of, 66–67
Efficacy of pediatric medicines
assessment of FDA reviews, 131–133
cost of tests for, 107
FDA requests for studies of, 128
historical evolution of regulatory framework, 29–30
historical evolution of research and labeling, 19–20, 20t
labeling changes supported by studies of, 194, 195t
national system for ensuring, 111–112
new product application and review, 65–67
orphan drug studies, 213
salient issues in analysis of, 28, 127–128, 261
sources of information on, 112–114
study outcomes to date, 2, 6, 26
template for, 128, 129b
terminology, 39
types of labeling changes based on, 197–203
See also Alternative endpoints; Endpoints, primary efficacy; Extrapolation of efficacy
Eletriptan, 184b
Elimination, drug, 45–47
Elixir Sulfanilamide, 29
Emphysema, 222b
eMPR, 280
Emtricitabine, 155b, 171t
Endpoints, primary efficacy, 12, 15, 39, 131–133. See also Alternative endpoints
Epocrates, 279
Esomeprazole magnesium, 122, 159, 163b, 169t
Etanercept, 294–295, 300, 304–305, 339t, 365t
Ethical issues
acceptance of studies conducted outside the United States, 92–93
in BPCA implementation, 89, 99–108
challenges in pediatric research, 22–23
clinical trial safeguards, 10
current state of pediatric research, 108–109
FDA resources to support, 96–99
FDA reviewer comments on, 102–103
historical evolution of pediatric research, 30–31
intergenerational justice, 11, 107
marketing exclusivity and, 11, 107–108
in medication testing with neonates, 142
need for safety and efficacy studies for, 20
in pharmacokinetic studies, 103–104
in placebo-controlled studies, 10, 104–106, 109
in PREA implementation, 89, 99–108
principles of pediatric drug studies, 89
protection of research participants, 90–96
restrictions on medical research, 10
suggestions for documentation of, 10, 109
Etodolac, 199b
Europe, research policies in
regulatory authority, 80–83
timelines for pediatric studies, 2, 6–7, 9, 26, 36, 82
See also International harmonization of research policies
European Medicines Agency, 9, 36, 79
Food and Drug Administration and, 81–83
Evidence-based practice, 20
Exclusivity, pediatric marketing
approval rate for, 14
based on active moiety, 74, 76
biologics coverage, 16, 207, 209, 210, 211, 228
duration, 209
eligible products, 74
ethical concerns, 11, 107–108
European approach, 81–82
FDA guidance, 33
frequency and outcomes of requests for, 180–181, 182t
legislative basis, 8–9, 32, 70
objectives, 71
Pediatric Research Equity Act and, 81
potential value of, 33, 107
public access to requests and reviews relating to, 100, 108
requirements for, 70–71, 73
scope of, 8, 32–33, 72–73, 76
second award, 74n
timeliness of FDA determination, 73
under Orphan Drug Act, 212
without labeling changes, 108, 179–181
Expertise in neonatal research and care, 162–163, 166, 187
Extemporaneous formulation, 50
Extrapolation of efficacy
decision tree for use of, 134, 135f
definition, 39–40
description of justification for use of, in requests and clinical reviews, 134–136, 140
extent and patterns of use, 12–13, 137–139, 137t, 138t, 140
FDA allowance for use of, 31, 56, 133–135
limitations, 273
options, 136–137
partial, 136–137n
rationale, 134
study goals, 5, 12, 24
suggestions for FDA public reports on acceptance of, 13, 140
Extrapolation of safety, 123–124
Exulizumab, 365t
F
Factor XIII concentrate, 212
Famotidine, 173t
Federal Food, Drug, and Cosmetic Act, 5, 25, 29, 30, 63, 64, 286
Fenoldopam, 149, 172t
Fentanyl, 153
Fibrin sealant, 339–340t, 375t
Fibrinogen, 376t
Fibrinogen concentrate, 341t
Fluconazole, 180, 273
Fluticasone propionate, 119–121, 199b
Food and Drug Administration
acceptance of extrapolated data in efficacy studies, 31, 56, 133–135
acceptance of studies conducted outside the United States, 92–93
advancement of regulatory science, 60
adverse events data, 11–12, 115–118
articulation of expected health benefits of requested studies, 15, 204
authorities and responsibilities, 4, 19, 34–35, 111, 286
basic regulatory framework, 64–70
capacity to impose sanctions for delayed studies, 15
data sources for analysis of pediatric research, 5–6, 189, 262–265
database of postmarket studies, 147n
definition of pediatric age group, 36–37, 63
documentation of research practices, 10
European Medicines Agency and, 81–83
evolution of pediatric drug research, 29–35
international harmonization of research policies, 36, 87
new drug application and review, 65–66
percentage of written requests initiated by, 182
postmarket surveillance requirements, 68–70
protections for human research participants, 90–96, 91b
requests for studies of off-patent products, 76–77
requirements for long-term studies, 61
resources in support of ethical standards in research, 96–99
suggestions for, 3, 10–11, 12, 13, 15, 109–110, 139, 140, 203, 204, 205
See also Best Pharmaceuticals for Children Act; Center for Biologics Evaluation and Research; Center for Drug Evaluation and Research; Clinical reviews by FDA; Pediatric Research Equity Act; Pediatric Rule
Food and Drug Administration Amendment Act, 24, 52, 69, 123, 180, 207, 213
Food and Drug Administration Modernization and Accountability Act, 8, 20, 32, 66, 70, 218n, 271
Food and Drug Administration Safety and Innovation Act, 64n
Forced expiratory volume measurement, 53, 131–133
Foreign research, 35–36. See also Europe, research policies in
Formulations for pediatric administration, 49–52
rationale for pediatric studies, 4, 21
Foundation for the National Institutes of Health, 77, 163, 188
Freedom of Information Act requests, 100
Fusion proteins, 289, 289t, 290
G
Gabapentin, 22b
Galsulfase, 341t, 365t
Gastroesophageal reflux disease, 133, 159–161, 182–183
Gatifloxacin ophthalmic, 122, 157, 158, 174t, 180
General Guidelines for the Evaluation of Drugs to Be Approved for Use During Pregnancy and for Treatment of Infants and Children, 30
Generic drugs, 71n
Golimumab, 341t, 365t
Government Accountability Office, 109
Griseofulvin, 115n
Guanfacine, 69, 122n, 199b
H
Harriet Lane Handbook, The, 274, 276, 279, 281
Hemangiomas, infantile, 17, 226, 227
Hemophilia, 294, 296–297
Hepatitis B immune globulin intravenous, 342t, 376t
Hepatitis C virus, 22–23b, 127, 212n
Hepatoblastoma, 143
HIV infection, 23b, 48, 150, 156–157, 201b
Human growth hormone, 65
Human Subject Protection/Bioresearch Monitoring Council, 98
Hyaluronidase recombinant human, 65
Hydrochlorothiazide, 164
Hydrocodone, 152
Hydrocortisone butyrate, 132b
Hydroxyethyl starch, 147n, 155b, 171t
Hypertension, 120b, 182–183, 185, 201b
written requests for studies, 381–385
I
Ibritumomab, 342t, 365t
Idursulfase, 343t, 366t
Immune deficiency syndromes, 298
Immune globulin
injection, 344t, 377t
intravenous, 217–218, 219, 220, 220n, 225b, 278–279, 294, 298, 345–346t, 347t, 376t, 377t
subcutaneous, 346–347t, 377t
types of, 292
See also Monoclonal antibodies
Immune thrombocytopenic purpura, 299
Incobotulinumtoxin A, 224b, 347t, 366t
Indication for use, 40
Inflammatory bowel disease, 305–308
Infliximab, 294–295, 302, 305, 306–307, 348t, 366t
Informed consent, 94
Inhalants, 51
Institutional review boards, 90, 93, 95, 98
Insulin, 65
Insulin glargine, 65
Insulin glulisine, 22b
Interchangeability of products, 208–209, 220n
Interferon, 22–23b, 127
Interferon alfacon-1, 225b, 349t, 366t
Interferon beta-1a, 349t, 366t
Interferon gamma-1b, 349t, 367t
Intergenerational justice, 11, 107
International harmonization of research policies, 9, 36, 76, 92
Investigational New Drug application, 65, 90, 215
Irinotecan hydrochloride, 121, 127, 202b
J
Juvenile idiopathic arthritis, 55, 120b, 201b, 299–302
K
Kawasaki disease, 298–299
Kefauver-Harris Amendments, 8, 29
L
Labeling of pediatric medicines
based on extrapolation from adult studies, 4, 12–13
biologics, 3, 5, 16–17, 27, 67–68, 217–218, 220–221, 228, 325–358t
clarity of changes in, 201–202, 202b, 203
clinician awareness of changes in, 203, 274–275
contents, 271
current shortcomings, 15, 273
data sources for analysis of, 5–6, 118, 119, 178, 262–264
definition of pediatric age group, 36, 40
effect of clinical reviews, 118, 119
evolution of regulatory framework, 29, 180
exclusivity without changes in, 108, 179–181
FDA requirements, 40, 67–68
format change, 16, 202–203, 204
historical evolution, 19–21, 20t, 31–32
indications for use, 40
limitations of legislative requirements, 273
need for long-term safety studies, 124–125
off-label use, 15–16, 204, 278–279, 280–281
one-year safety reviews after changes in, 125–126
outcomes of legislation to date, 2–3, 27
outcomes of neonatal assessments, 13, 146–148, 153–163, 157t, 168–175t
pharmacogenetic information, 48–49
public access to information regarding, 100–101, 272, 274
published literature inconsistent with, 101
regulatory definition, 40
salient issues in safety and efficacy analysis, 5, 24
scope and outcomes of requested changes in, 14–16, 34, 177–180, 178f
sources of prescribing information for clinicians, 276–281, 277–278t, 281t, 282
suggestions for access to studies leading to changes in, 10–11, 110
suggestions for clarifying, 16, 204
suggestions for follow-up safety studies after changes in, 12, 139
time from initiation of study to, 149
types of changes in, 197–203
types of studies supporting changes in, 194, 195t
for use with neonates, 144
Lamivudine, 172t
Lamotrigen, 92n
Lansoprazole, 159, 162b, 169t
Laronidase, 350t, 367t
Leflunomide, 119, 196, 198b
Levalbuterol hydrochloride, 132–133
Lexi-Comp, 279
Lindane, 96
Linezolid, 171t
Long-term outcomes
biologics use, 313
current shortcomings in pharmaceutical research, 2, 7, 26–27, 167
data sources, 25
developmental psychopharmacology considerations, 61
FDA database of postmarket studies, 147n
neonatal research, 142, 143, 167
one-year safety reviews, 125–126
required postmarket safety studies, 126–127
research rationale, 124–125
suggestions for safety studies, 12, 139
Lopinavir-ritonavir, 143–144, 156, 171t
M
Make Medicines Child Size, 36
Malaria, 213–214
MD Consult, 279–280
MedGuides, 272
Medscape/WebMD/eMedicine, 279
MedWatch, 68
Meropenem, 274–275
Methadone, 164
Methylphenidate, 48, 132b
Metronidazole, 164–165
Micafungin, 273
Micromedex, 279
Migraine, 121, 182–183, 184b, 198b
Mometasone furoate, 121, 202b
Monoclonal antibodies, 288–290, 289t, 292–293, 311
Monthly Prescribing Reference, 280
Moxifloxacin, 157–158, 172t
N
Natalizumab, 350t, 367t
National Academy of Sciences, 30
National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 30–31
National Institute of Child Health and Human Development, 59, 164–165, 188
National Institutes of Health
biologics regulation in, 29–30
neonate studies, 14, 163–164, 164t, 166–167
in orphan drug development, 213
pediatric drug development program under BPCA, 8–9, 31, 35, 76–77, 188
scope of pdiatric research activities, 35, 59–60
suggestions for, 14, 166–167
National Library of Medicine, 110
National Research Council, 30
Nelfinavir, 172t
Nelson’s Pocket Book of Pediatric Antimicrobial Therapy, 279
Neofax, 278, 279, 281
Neonatal assessment tools, 146
Neonatal medicine
analgesia drugs, 143, 146
assessment tools, 146
challenges of medication testing, 142–144
current shortcomings in pharmaceutical research, 2, 7, 13, 26–27, 141
deferred studies, 152
developmental pharmacology, 46
FDA expertise for study assessments, 162–163, 166
gestational age, 142
labeling, 153–163, 168–175t
long-term investigations, 142, 143, 167
medications commonly used in intensive care, 144–146, 145t
National Institutes of Health studies, 14, 163–164, 166–167
number and origins of studies, 146–149, 165–166
outcomes of BPCA studies, 165–167
PREA requirements, 151–153
rationale for medication studies, 13–14, 141, 144
suggestions for improving pharmaceutical research, 3, 14, 166–167
variability within age groups, 142
waivers from clinical assessment requirements, 13, 151–153, 151n
written requests under BPCA, 149–151
Nevirapine, 23b, 170t
New Drug Application, 9, 65–67, 98, 114, 151, 188
pediatric exclusivity program, 70–74
priority review, 213
Newborn Drug Development Initiative, 164
Nitric oxide, 119, 149, 168t
O
Ofatumumab, 350t, 367t
Office of Good Clinical Practice, 98
Office of New Drugs, 97
Office of Pediatric Therapeutics, 83–84, 97, 274
Off-label use
ambiguous labeling, 15–16, 204, 278–279, 280–281
data sources for evaluation of, 19–20, 25
definition, 40
ethical issues in, 20
with neonates, 14, 141–142, 144
prevention of, 26
as source of adverse events, 44, 272
Off-patent products, 35, 76–77, 163, 188
Ofirmev, 168t
Ofloxacin, 158, 175t
Olmesartan, 120b, 202b
Omalizumab, 23b, 37, 120b, 122–123, 151, 198b, 351t, 368t
Omeprazole, 159
Ondansetron, 152
One-year safety reviews, 25, 125–126
Oprelvekin, 351t, 368t
Orphan Drug Act, 3, 9, 16, 27, 34–35, 209, 211, 212–213, 228
Orphan drugs, 34–35
biologics, 16, 221
efficacy studies, 213
European rules, 82–83
exclusivity incentives for, 212
neonate studies, 147
pediatric approvals, 16, 212
postmarket studies, 212
quality of studies in support of, 213
Osteogenesis imperfecta, 57, 76, 121, 130
Otelixizumab, 311
Overweight and obese children, 47
Oxycodone, 152
P
Palifermin, 351t, 368t
Palivizumab, 352t, 369t
Pancrelipase, 123–124
Panitumumab, 352t, 369t
Pantoprazole, 52, 133, 138–139, 159, 162–163b, 169t
Parental consent for child research subjects, 94
Patient Protection and Affordable Care Act, 24, 34, 207, 261
Pediatric Academic Societies, 59
Pediatric Advisory Committee, 25, 84, 96, 125, 272
Pediatric and Maternal Health Staff, 97
Pediatric Labeling Rule, 31
Pediatric Pharmacology and Therapeutics Research Consortium, 59
Pediatric plan
requirements for, 78–79
suggested change in requirements for, 9, 87
Pediatric research, generally
age range definition, 4–5, 36–37, 63
benefits, 2, 6, 15, 22–23b, 26
consideration of developmental variability, 49–58
current shortcomings, 2, 6, 15, 26–27
economic incentives, 1, 3, 8–9, 19, 32–33
ethical issues in, 10–11
historical evolution, 19–20, 20t, 29–36, 63
legislative mandates, 1, 3, 8, 9, 19, 33
obstacles and disincentives, 4, 21–23, 271
outside the United States, 35–36, 92–93
protections for pediatric research participants, 93–96
rationale, 4, 20–21, 43–44
risk assessment, 91b, 95–96, 118, 121–123
salient issues, 1–2, 5, 24–25, 28, 261–262
strategies for improving, 2, 3–4, 15, 19, 32, 204–205, 271–272
suggestions for improving, 3
types of studies, 37–39
See also Neonatal assessment tools
Pediatric Research Equity Act, 62
age range covered by, 4–5
approval letters, 188–189, 190
Best Pharmaceuticals for Children Act and, 34, 81
biologics coverage under, 3, 16, 27, 207, 214–215, 228
clinical reviews, 112–114
cost-benefit analysis, 109
creation of, 33, 77
data sources for analysis of, 112, 189
deferral of pediatric assessments, 79, 189, 190, 191–193, 192t
deficiencies resulting in inadequate studies, 195–197, 198–199b, 203
effects on clinical practice, 25
ethical implementation, 89, 99–108
FDA administrative structure for, 83–84
labeling changes attributed to, 178
neonatal assessments under, 141, 148, 151–153, 165–167
objectives, 1, 19, 77, 111, 271–272
one-year safety reviews, 125–126
orphan product exemptions, 212
outcomes to date, in pharmaceutical safety and effectiveness, 2–3, 6–8, 26–27
pediatric plan, 78–79
primary provisions, 9, 78
proposal for permanent reauthorization, 86–87
public access to studies conducted under, 10–11, 84–86, 100–102, 109, 112, 272
reauthorizations, 3, 7, 9, 27, 87
requests for studies of off-patent products, 77
requirements for biologics research, 3, 7–8
retroactive application, 81
safeguards for pediatric research, 10
salient issues in analysis of, 1, 5, 24, 28, 261–262
scope and outcomes of requested labeling changes, 14–16, 22–23b, 34, 177–180, 178f, 194, 195t
scope and outcomes of required studies, 2, 188–193, 203
specifications for types of required studies, 190–191
suggestions for improving, 3
types of labeling changes made under, 197–203
use of extrapolation studies under, 137, 138t
waiver of pediatric assessment requirements, 80–81, 80t, 189–190
Pediatric Review Committee, 9–10, 84, 97, 115, 189, 194
Pediatric Rule, 9, 33, 77, 81, 262, 271–272
biologics coverage under, 214
Pediatric Trials Network, 59
Pegfilgrastim, 196–197, 352t, 369t
Peginterferon alfa-2a, 212n, 353t, 369t
Peginterferon alfa-2b, 354t, 370t
Pegloticase, 225b, 354t, 370t
Pharmaceutical industry
economic incentives for pediatric research, 1, 3, 8–9
FDA terminology, 41
penalties for delayed studies, 15
percentage of written requests initiated by, 182
as source of prescribing information for clinicians, 276
uncertainty arising from reauthorizations of laws, 3, 7, 27
See also Exclusivity, pediatric marketing
Pharmaceutical research and development
additives, 50
definition of drug, 64
drug formulation and delivery systems, 49–52
ethical issues in pediatric studies, 10–11
evolution of regulatory framework, 29–36
FDA application and review, 65–67
generic drugs, 71n
legislative requirements, 9
obstacles and disincentives to, 4, 21–23
pediatric plan, 78–79
pharmacogenetic considerations, 48–49
postmarket monitoring, 68–70
product labeling requirements, 67–68
types of studies for, 37–38
See also Neonatal medicine; Pediatric research, generally
Pharmacodynamics
challenges in neonatal research, 142, 143
rationale for pediatric studies, 4, 21
Pharmacogenomics, 48–49
Pharmacokinetics
approaches to pediatric research, 56–57
biologics data, 292–293
challenges in neonatal research, 142, 143
cost of studies, 107
developmental pharmacology, 44–48
disease conditions affecting, 47
ethical practice in pediatric studies of, 103–104
extrapolation from adult studies, 13
genetic variability, 48–49
labeling changes supported by studies of, 194, 195t
rationale for pediatric studies, 4, 21
shortcomings of pediatric knowledge base, 292
study outcomes to date, 2, 6, 26
Physicians’ Desk Reference, 279
Placebo studies, 10, 58, 104–106, 109
Postmarket monitoring, 68–70
public access to information about, 191–193
required safety studies, 126–127
Postmarket study commitments, 38
Pralidoxime chloride, 179
Premature or low-birthweight infants
chloramphenicol treatment, 43–44
current shortcomings in pharmaceutical research, 2, 7
developmental pharmacology, 46–47
Priority review vouchers, 213–214
Propofol, 198b
Protein-based biologics, 210
Protein C concentrate, 354t, 377t
Proton pump inhibitors, 159–161
Pseudobulbar effect, 133
Pseudophedrine, 152
Psoriasis, 303–305
Public access to information
about abandoned or incomplete studies, 101
biologics applications and reviews, 215
current requirements for BPCA and PREA, 84–86, 100–102, 112
deferral of pediatric assessments, 79, 191
on labeling changes, 100–101, 272, 274
redaction of FDA documents, 2–3, 6, 7, 10–11, 27, 100, 102, 109–110, 118, 119, 158
on studies earning exclusivity, 100, 108
suggestions, 3, 10–11, 13, 109–110, 140
Public Health Service Act, 5, 25, 63, 64, 207, 208, 286
PubMed, 11, 102, 110
Pure Food and Drugs Act, 29
Q
Quinidine sulfate, 133
R
Rabeprazole, 159
Ranibizumab, 224b, 354t, 370t
Ranitidine, 174t
Rasburicase, 370t
Reauthorizations of BPCA and PREA, 3, 7, 9, 27, 33, 86–87
Recombinant-derived therapeutics, 288–290, 291–292t
Recruitment for research, 2, 4, 21–22, 58, 59–60, 142, 196–197
Red Book, The, 279
Redaction of FDA documents, 2–3, 6, 7, 10–11, 27, 100, 102, 109–110, 118, 119, 158
Regulatory science, 60
Remifentanil, 172t, 200b
Research designs
acceptance of studies conducted outside the United States, 92–93
adaptive designs for pediatric studies, 57–58
age-group selection, 55–56
biospecimen sampling, 54–55
challenges of medication testing with neonates, 142–144
current shortcomings, 2, 6, 15, 26
developmental considerations, 52, 54–58
obstacles to pediatric research, 4, 21–22
pharmacogenetic considerations in, 48–49
placebo-controlled studies, ethics considerations in, 10, 58, 104–106
protection of human research participants, 90–96
randomized withdrawal, 58, 106
strategies for improving, 2, 15, 204–205
written requests for hypertension studies, 381–385
See also Alternative endpoints
Rheumatoid arthritis, 119, 196, 198b, 199b
Rho(D) immune globulin intravenous, 217–218, 225b, 355t, 378t
Ribavirin, 127
Rickettsia, 43–44
Rifapentine, 104n
Rilanocept, 356t, 370t
Rilpivirine, 152
RimabotulinumtoxinB, 223b, 356t, 370t
Risedronate, 76
Risk-benefit assessments
analysis of clinical reviews of pediatric studies, 118, 121–123
ethics issues, 90, 91b, 93, 94b, 95–96, 97, 99, 103–104
long-term studies, 61
structured framework for, 123
suggestions for, 12, 139
terminology, 39
Rituximab, 309, 312, 356t, 371t
Rocuronium bromide, 154–155b, 155–156, 169t
Romiplostim, 223b, 356t, 371t
Rusbiricase, 355t
S
Safety of pediatric medicines, 28
analysis of clinical reviews of pediatric studies, 117–123
biologics, 294–295
clinical trials assessment and monitoring, 114–115, 117
cost of tests for, 107
extrapolation from adult studies, 123–124
historical evolution of regulatory framework, 29–36
historical evolution of research and labeling, 19–20, 20t
labeling changes supported by studies of, 194, 195t
national system for ensuring, 111–112
need for long-term studies, 124–125
new product application and review, 65–67
one-year reviews, 125–126
quality of FDA studies, 11–12
required postmarket studies, 126–127
sources of information on, 112–114
study outcomes to date, 2, 6, 26
substantial evidence of, 66–67
suggestions for long-term follow-up studies, 12, 139
suggestions for use of template for clinical reviews, 12, 139
terminology, 39
types of labeling changes based on, 197–203
Salmeterol xinafoate, 119–121
Salmonella, 43–44
Sanctions and penalties for delayed studies, 15, 79
Schizophrenia, 120b, 127, 202b
Secretary of Department of Health and Human Services, 5, 24, 70–71
Sevoflurane, 174t
Sipuleucel T, 225b, 356t, 378t
Smallpox vaccine, 29
Somatropin recombinant, 65
Sotalol hydrochloride, 50, 56–57, 122, 149, 173t, 199b
Statins, 61
Stavudine, 173t
Study Endpoint and Labeling Development Group, 130
Substantial evidence of safety and effectiveness, 66–67
Subtherapeutic dosing, 96
Suggestions for
biologics research, 3, 12, 16, 139, 229
clarity of labeling, 16, 204
data sources and methodology for development of, 25
documentation of ethical practice, 109
dosing research, 15, 203
expanded public access to information, 3, 10–11, 109–110, 140
format and content of safety and efficacy studies, 3, 12, 13, 15, 139, 140, 204
improving pediatric studies of drugs and biologics, 15, 205
neonatal drug studies, 3, 14, 166–167
placebo-controlled trials
postmarket follow-up studies, 12, 139
reporting on use of endpoints in pediatric studies, 12, 140
timeliness of pediatric studies, 3, 9, 15, 26, 87
Sumatriptan, 184b
Surrogate endpoints, 53, 129–130, 130n
T
Tarascon Pharmacopoeia, 279
Telithromycin, 99
Tenecteplase, 356t, 372t
Tenofovir disoproxil fumarate, 119, 122, 147n, 201b
Teplizumab, 311–312
Terbinafine hydrochloride, 51
Thalidomide, 29
Thrombin, topical, 357t, 378t
Timeliness of processes, 2, 6–7, 9, 26
deferral of PREA studies, 191–193, 192t
European medical research requirements, 82
FDA capacity to impose sanctions for delayed studies, 15
FDA determination of exclusivity awards, 73
FDA requirements, 82
international harmonization of regulations, 87
public access to information about, 191–193
suggestions, 3
from study initiation to labeling change, 149
time from written request to completed review, 87
Tinea capitis, 51
Tocilizumab, 300, 301–302, 357t, 372t
Tositumomab and iodine, 225b, 357t, 372t
Trastuzumab, 357t, 372t
Tropical disease drugs, 213–214
Tumor necrosis factor inhibitors, 294–295
U
Ulcerative colitis, 305–308
Update of the American Academy of Pediatrics, 274
UpToDate, 279–280
U.S. Congress, 2–3, 7, 9–10, 27, 33, 34, 84–85, 86, 87, 100, 125, 204, 274
suggestions for, 3, 10–11, 14, 15, 109–110, 166–167, 229
Ustekinumab, 358t, 372t
V
Vaccines, 29, 215, 264, 285, 322–323
adverse event monitoring, 68–69
Vaccinia immune globulin intravenous, 358t, 378t
Valganciclovir, 52, 102–103, 169t
Vinorelbine tartrate, 200b
Vitamin E, 142
von Willebrand factor, 358t, 379t
W
Waivers
for neonatal assessment, 13, 151–153, 151n
of pediatric assessment requirements, 80–81, 80t
for pediatric formulation, 52
pediatric studies of biologics with, 221, 222–223b
rationale under PREA, 189–190
Water soluble drugs, 45
WebMD, 279
World Health Organization, 36
X
Xigris, 364t
Z
Zidovudine, 177
Zoledronic acid, 57, 202b
Zolmitriptan, 184b, 198b