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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

Index

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×

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

Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
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Suggested Citation:"Index." Institute of Medicine. 2012. Safe and Effective Medicines for Children: Pediatric Studies Conducted Under the Best Pharmaceuticals for Children Act and the Pediatric Research Equity Act. Washington, DC: The National Academies Press. doi: 10.17226/13311.
×
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The Best Pharmaceuticals for Children Act (BPCA) and the Pediatric Research Equity Act (PREA) were designed to encourage more pediatric studies of drugs used for children. The FDA asked the IOM to review aspects of pediatric studies and changes in product labeling that resulted from BPCA and PREA and their predecessor policies, as well as assess the incentives for pediatric studies of biologics and the extent to which biologics have been studied in children. The IOM committee concludes that these policies have helped provide clinicians who care for children with better information about the efficacy, safety, and appropriate prescribing of drugs. The IOM suggests that more can be done to increase knowledge about drugs used by children and thereby improve the clinical care, health, and well-being of the nation's children.

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