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From page 395... ... , 190, 327t, 372t Adalimumab, 120b, 132b, 151, 201b, Albuterol sulfate, 57, 133 294–295, 300–301, 307, 326t, 360t Alefacept, 327t, 360t Adolescents Alemtuzumab, 327t, 360t developmental pharmacology, 47 Alendronate, 121, 132b in pediatric age range, 47 Alglucosidase alfa, 212, 213, 327–328t, Adults, pediatric drug use based on studies 361t with Almotriptan, 103, 121, 184b analysis of clinical reviews of, 119, 120b Alpha1-proteinase inhibitor, 222b, 224b, extrapolation of safety in, 123–124 328–329t, 372–373t risks in, 4, 30, 273 Alternative endpoints See also Alternative endpoints; composite endpoints as, 53–54 Extrapolation of efficacy definition, 12, 39, 128–129 Adverse Event Reporting System, 68, 272 study goals, 5, 12 Adverse events suggestions for reporting on use of, in data sources, 11–12 studies, 12, 140 definition, 11, 39, 115–117 395 Read the entire page →
From page 396... ... v. FDA, 33 public access to studies conducted under, Asthma, 21, 23b, 48, 51, 120b, 121, 3, 11, 84–86, 100–102, 109, 112, 132–133, 198b, 202b 272 Atopic dermatitis, 302–303 reauthorizations, 3, 7, 9, 27, 87 Attention deficit hyperactivity disorder, 48, requests for studies of off-patent 69, 122n, 125, 199b products, 76–77 Autism, 151n safeguards for pediatric research, 10 Autologous cultured chondrocytes, 331t, salient issues in analysis of, 1, 5, 24, 28, 374t 261–262 Azithromycin, 164 scope and outcomes of studies under, 2, 14–16, 22b, 23b, 34, 74–76, 177–183, 178f, 182f, 203 B sources of requests, 182, 226 strategies for improving, 3, 166–167 Basilixmab, 332t, 361t suggestions for neonatal assessments Becaplermin, 224b, 226, 227, 332t, 361t under, 14, 166–167 Belmont Report, 30–31 types of labeling changes made under, Benzyl alcohol, 30 197–203 Besifloxacin ophthalmic, 158–159 Betamethasone, 164 Best Pharmaceuticals for Children Act Better Pharmaceutical for Children, 32 age range covered by, 4–5 Bevacizumab, 309, 332t, 362t biologics coverage added, 3, 7–8, 16, 27, Biologics 34, 207 access to application and review data, biologics with possible promise for 215 pediatric study, 226 approval letters, 218 clinical reviews, 112–114 Read the entire page →
From page 397... ... 397 INDEX biosimilarity and interchangeability, See also Biologics License Application; 208–209 Center for Biologics Evaluation and clinical pharmacology, 292–293 Research; Vaccines clinical trials registry, 219–220, Biologics Control Act, 29, 285 359–379t Biologics License Application, 9, 65–66, current pediatric labeling, 3, 16–17, 27, 114, 151, 188, 209 217–218, 220–221, 228 priority review, 213 data sources for analysis of pediatric supplemental, 209 research, 6, 178, 215–220, 263, Biologics Price Competition and Innovation 321–324 Act, 2, 5, 24, 63, 207, 208–211, definition, 7n, 64–65, 208n, 210, 286 214–215, 228–229, 262 developmental pharmacology, 313 Biosimilar products, 208–209 extension of BPCA to, 3, 16, 27, 34, 63, Biospecimen sampling, 54–55 207, 208–215 Bipolar disorder, 127 future prospects, 17, 228–229 Bivalirudin, 174t, 180 historical and technical evolution, Botulism immune globulin, 41, 333t, 374t 285–286 Bronchopulmonary dysplasia, 119, 129, 149 labeling information on FDA-approved Buspirone hydrochloride, 132b, 138, 202b products, 220–221, 325–358t labeling requirements, 67–68 C market exclusivity protections for, 71–73, 207, 209, 210, 211, 228 C1 esterase inhibitor, 333t, 374t mechanism of action, 290 Caffeine citrate, 144–145 neonate studies, 146–147 California Department of Health Services, Orphan Drug Act and, 34, 78, 212–213, 41 228 Canakinumab, 334t, 363t outcomes to date of legislative Cancer, 308–310, 312–313 requirements for research on, 3, 7–8, Candesartan, 201b 27 Candidiasis, 273 plasma-derived, 287–288, 288t, 293, Caspofungin, 170t 294 Ceftaroline fosamil, 152 PREA requirements for, 7, 16, 33, 78, Ceftriaxone, 143 207, 214–215, 222–223b Center for Biologics Evaluation and priority review vouchers, 213–214 Research, 29–30, 83, 84, 97, 112, products not tested for pediatric use, 5, 114, 180, 193, 216, 286 215, 222–226, 224–225b suggestions for, 12, 139 products studied with children, 7–8, 27, Center for Devices and Radiological Health, 220–221, 221t, 359–379t 97 products with possible promise for Center for Drug Evaluation and Research, pediatric study, 226–227, 228 12, 83, 84, 97, 112–114, 115, 128, recombinant-derived, 288–290, 130, 180, 193, 286 291–292t Certolizumab pegol, 334t, 363t safety concerns, 294–295 Cetuximab, 309, 334t, 363t salient issues in pediatric medicine, 1, 2, Children's Health Act, 93, 309 5, 24–25, 207–208, 262 Children's Oncology Group, 59, 196–197 sources of, 286–287 Chloramphenicol, 43–44, 90, 141 structure, 287, 287f Ciprofloxacin, 158, 174t suggestions for research, 3, 16, 229 Cisapride, 101 supplemental license applications, 209 Clinical and Translational Science Awards, therapeutic applications, 296–313 59 types of, 287–290 Read the entire page →
From page 398... ... 398 INDEX Clinical practice, 25, 39 support infrastructure for pediatric clinician awareness of labeling changes, research, 58–60 274–275 trial design, 56–58 sources of prescribing information, types of, 38b 276–281, 277–278t, 281t, 282 See also ClinicalTrials.gov Clinical reviews by FDA ClinicalTrials.gov, 11, 85, 102, 110, 219, analysis of efficacy assessments in, 323 131–133 Clopidogrel, 58, 149, 154b analysis of safety assessments in, 11, Coagulation factor IX, 335t, 375t 117–123 Coagulation factor VIIa, 335t, 374t audience, 113–114 Collagenase clostridium histolyticum, 225b, as data source, 112–113 335t, 363t definition, 112–113 Composite endpoints, 53–54 description of endpoints in, 12, Confidentiality and privacy 131–133, 194 protections for research subjects, 90 description of research design and redactions in clinical reviews to protect, integrity in, 10, 100, 102–103, 109 193 discussion of developmental variability, Conflict of interest, 90, 102 194 Conjunctivitis, 101, 147, 153, 157–159 effects on labeling, 118, 119 Corticosteroids, 48 efficacy review template, 128, 129b Cost-benefit analysis of BPCA and PREA, justification for use of extrapolation of 109 efficacy in, 13, 134–136 Creating Hope Act, 213 public access to, 13, 109, 112 Crohn's disease, 305–308 quality of, 112, 114, 139, 193–194 Crotalidae polyvalent immune Fab, 217, redacted material, 10–11, 100, 102, 336t, 375t 109–110, 118, 119, 158, 193 Cystic fibrosis, 35 safety review template, 12, 115, 116b, Cystic Fibrosis Foundation, 60 139, 193 Cystic Fibrosis Therapeutic Development scope of, 113 Network, 60 sources of, 112 Cytochrome enzymes, 45, 46 suggestions for, 10, 12, 139 Cytomegalovirus, 103 template for reviews, 113b Clinical trials D abandoned, 101 conducted outside the United States, Daclizumab, 336t, 364t 92–93 Darbepoetin, 337t, 364t data integrity, 91 Darunavir, 150 database, 219n Data monitoring committee, 114–115 definition, 37–38 Declaration of Helsinki, 92, 104 drug delivery documentation, 51 Denileukin diftitox, 337t, 364t ethical issues in, 10 Denosumab, 337t, 364t limits of short-term studies, 61 Department of Health and Human Services, for pediatric populations, 55–56 90, 93 pharmacogenetic considerations in, Desflurane, 120b, 128, 200b, 203 48–49 Developmental pharmacology protection of research participants, of biologics, 313 90–96 consideration of, in FDA reviews, 194 registry, 219–220, 359–379t implications for drug formulation and safety assessment and monitoring in, delivery, 49–52 114–115, 117 Read the entire page →
From page 399... ... 399 INDEX implications for pediatric research labeling changes supported by studies of, design, 54–58 194, 195t long-term use of drugs, 61 national system for ensuring, 111–112 pharmacogenetic factors, 48–49 new product application and review, research support infrastructure for 65–67 consideration of, 58–60 orphan drug studies, 213 in selection of endpoint measures, 52–54 salient issues in analysis of, 28, significance of, 44–48, 49 127–128, 261 Dextromethorphan hydrobromide, 133 sources of information on, 112–114 Diabetes, 22b, 310–312, 313 study outcomes to date, 2, 6, 26 Didanosine, 156, 173t template for, 128, 129b Diethylene glycol, 29 terminology, 39 Difluprednate ophthalmic solution, 147n types of labeling changes based on, Digoxin immune Fab, 338t, 375t 197–203 Diphtheria antitoxin, 29 See also Alternative endpoints; Division of Scientific Investigations, 98, 102 Endpoints, primary efficacy; Dosing Extrapolation of efficacy clinician access to new information on, Eletriptan, 184b 274 Elimination, drug, 45–47 developmental pharmacology, 46 Elixir Sulfanilamide, 29 extrapolation of pediatric dose from Emphysema, 222b adult studies, 4, 273, 273t eMPR, 280 label guidelines for off-label pediatric Emtricitabine, 155b, 171t use, 15–16, 204 Endpoints, primary efficacy, 12, 15, 39, sources of prescribing information 131–133. See also Alternative for pediatric clinicians, 276–281, endpoints 277–278t, 281t, 282 Epocrates, 279 subtherapeutic, 96 Esomeprazole magnesium, 122, 159, 163b, suggestions for pediatric research, 15, 169t 203 Etanercept, 294–295, 300, 304–305, 339t, See also Developmental pharmacology 365t Drotrecogin alfa, 338t Ethical issues Drug Facts and Comparisons, 279 acceptance of studies conducted outside Drugs, definition of, 64 the United States, 92–93 Drugs@FDA, 100, 274 in BPCA implementation, 89, 99–108 challenges in pediatric research, 22–23 clinical trial safeguards, 10 E current state of pediatric research, 108–109 Ecallantide, 339t, 364t FDA resources to support, 96–99 Eculizumab, 339t FDA reviewer comments on, 102–103 Effectiveness of medical intervention, 39 historical evolution of pediatric research, substantial evidence of, 66–67 30–31 Efficacy of pediatric medicines intergenerational justice, 11, 107 assessment of FDA reviews, 131–133 marketing exclusivity and, 11, 107–108 cost of tests for, 107 in medication testing with neonates, 142 FDA requests for studies of, 128 need for safety and efficacy studies for, historical evolution of regulatory 20 framework, 29–30 in pharmacokinetic studies, 103–104 historical evolution of research and in placebo-controlled studies, 10, labeling, 19–20, 20t 104–106, 109 Read the entire page →
From page 400... ... 400 INDEX in PREA implementation, 89, 99–108 extent and patterns of use, 12–13, principles of pediatric drug studies, 89 137–139, 137t, 138t, 140 protection of research participants, FDA allowance for use of, 31, 56, 90–96 133–135 restrictions on medical research, 10 limitations, 273 suggestions for documentation of, 10, options, 136–137 109 partial, 136–137n Etodolac, 199b rationale, 134 Europe, research policies in study goals, 5, 12, regulatory authority, 80–83 24 timelines for pediatric studies, 2, 6–7, 9, suggestions for FDA public reports on 26, 36, 82 acceptance of, 13, 140 See also International harmonization of Extrapolation of safety, 123–124 research policies Exulizumab, 365t European Medicines Agency, 9, 36, 79 Food and Drug Administration and, F 81–83 Evidence-based practice, 20 Factor XIII concentrate, 212 Exclusivity, pediatric marketing Famotidine, 173t approval rate for, 14 Federal Food, Drug, and Cosmetic Act, 5, based on active moiety, 74, 76 25, 29, 30, 63, 64, 286 biologics coverage, 16, 207, 209, 210, Fenoldopam, 149, 172t 211, 228 Fentanyl, 153 duration, 209 Fibrin sealant, 339–340t, 375t eligible products, 74 Fibrinogen, 376t ethical concerns, 11, 107–108 Fibrinogen concentrate, 341t European approach, 81–82 Fluconazole, 180, 273 FDA guidance, 33 Fluticasone propionate, 119–121, 199b frequency and outcomes of requests for, Food and Drug Administration 180–181, 182t acceptance of extrapolated data in legislative basis, 8–9, 32, 70 efficacy studies, 31, 56, 133–135 objectives, 71 acceptance of studies conducted outside Pediatric Research Equity Act and, 81 the United States, 92–93 potential value of, 33, 107 advancement of regulatory science, public access to requests and reviews 60 relating to, 100, 108 adverse events data, 11–12, 115–118 requirements for, 70–71, 73 articulation of expected health benefits scope of, 8, 32–33, 72–73, 76 of requested studies, 15, 204 second award, 74n authorities and responsibilities, 4, 19, timeliness of FDA determination, 73 34–35, 111, 286 under Orphan Drug Act, 212 basic regulatory framework, 64–70 without labeling changes, 108, 179–181 capacity to impose sanctions for delayed Expertise in neonatal research and care, studies, 15 162–163, 166, 187 data sources for analysis of pediatric Extemporaneous formulation, 50 research, 5–6, 189, 262–265 Extrapolation of efficacy database of postmarket studies, 147n decision tree for use of, 134, 135f definition of pediatric age group, 36–37, definition, 39–40 63 description of justification for use of, documentation of research practices, 10 in requests and clinical reviews, European Medicines Agency and, 81–83 134–136, 140 Read the entire page →
From page 401... ... 401 INDEX evolution of pediatric drug research, Gatifloxacin ophthalmic, 122, 157, 158, 29–35 174t, 180 international harmonization of research General Guidelines for the Evaluation policies, 36, 87 of Drugs to Be Approved for Use new drug application and review, 65–66 During Pregnancy and for Treatment percentage of written requests initiated of Infants and Children, 30 by, 182 Generic drugs, 71n postmarket surveillance requirements, Golimumab, 341t, 365t 68–70 Government Accountability Office, 109 protections for human research Griseofulvin, 115n participants, 90–96, 91b Guanfacine, 69, 122n, 199b requests for studies of off-patent products, 76–77 H requirements for long-term studies, 61 resources in support of ethical standards Harriet Lane Handbook, The, 274, 276, in research, 96–99 279, 281 suggestions for, 3, 10–11, 12, 13, 15, Hemangiomas, infantile, 17, 226, 227 109–110, 139, 140, 203, 204, 205 Hemophilia, 294, 296–297 See also Best Pharmaceuticals for Hepatitis B immune globulin intravenous, Children Act; Center for Biologics 342t, 376t Evaluation and Research; Center Hepatitis C virus, 22–23b, 127, 212n for Drug Evaluation and Research; Hepatoblastoma, 143 Clinical reviews by FDA; Pediatric HIV infection, 23b, 48, 150, 156–157, 201b Research Equity Act; Pediatric Rule Human growth hormone, 65 Food and Drug Administration Amendment Human Subject Protection/Bioresearch Act, 24, 52, 69, 123, 180, 207, 213 Monitoring Council, 98 Food and Drug Administration Hyaluronidase recombinant human, 65 Modernization and Accountability Hydrochlorothiazide, 164 Act, 8, 20, 32, 66, 70, 218n, 271 Hydrocodone, 152 Food and Drug Administration Safety and Hydrocortisone butyrate, 132b Innovation Act, 64n Hydroxyethyl starch, 147n, 155b, 171t Forced expiratory volume measurement, 53, Hypertension, 120b, 182–183, 185, 201b 131–133 written requests for studies, 381–385 Foreign research, 35–36. See also Europe, research policies in Formulations for pediatric administration, I 49–52 rationale for pediatric studies, 4, 21 Ibritumomab, 342t, 365t Foundation for the National Institutes of Idursulfase, 343t, 366t Health, 77, 163, 188 Immune deficiency syndromes, 298 Freedom of Information Act requests, 100 Immune globulin Fusion proteins, 289, 289t, 290 injection, 344t, 377t intravenous, 217–218, 219, 220, 220n, 225b, 278–279, 294, 298, 345–346t, G 347t, 376t, 377t subcutaneous, 346–347t, 377t Gabapentin, 22b types of, 292 Galsulfase, 341t, 365t See also Monoclonal antibodies Gastroesophageal reflux disease, 133, Immune thrombocytopenic purpura, 299 159–161, 182–183 Incobotulinumtoxin A, 224b, 347t, 366t Read the entire page →
From page 402... ... 402 INDEX Indication for use, 40 effect of clinical reviews, 118, 119 Inflammatory bowel disease, 305–308 evolution of regulatory framework, 29, Infliximab, 294–295, 302, 305, 306–307, 180 348t, 366t exclusivity without changes in, 108, Informed consent, 94 179–181 Inhalants, 51 FDA requirements, 40, 67–68 Institutional review boards, 90, 93, 95, 98 format change, 16, 202–203, 204 Insulin, 65 historical evolution, 19–21, 20t, 31–32 Insulin glargine, 65 indications for use, 40 Insulin glulisine, 22b limitations of legislative requirements, Interchangeability of products, 208–209, 273 220n need for long-term safety studies, Interferon, 22–23b, 127 124–125 Interferon alfacon-1, 225b, 349t, 366t off-label use, 15–16, 204, 278–279, Interferon beta-1a, 349t, 366t 280–281 Interferon gamma-1b, 349t, 367t one-year safety reviews after changes in, Intergenerational justice, 11, 107 125–126 International harmonization of research outcomes of legislation to date, 2–3, 27 policies, 9, 36, 76, 92 outcomes of neonatal assessments, 13, Investigational New Drug application, 65, 146–148, 153–163, 157t, 168–175t 90, 215 pharmacogenetic information, 48–49 Irinotecan hydrochloride, 121, 127, 202b public access to information regarding, 100–101, 272, 274 published literature inconsistent with, J 101 regulatory definition, 40 Juvenile idiopathic arthritis, 55, 120b, salient issues in safety and efficacy 201b, 299–302 analysis, 5, 24 scope and outcomes of requested changes in, 14–16, 34, 177–180, K 178f sources of prescribing information for Kawasaki disease, 298–299 clinicians, 276–281, 277–278t, 281t, Kefauver-Harris Amendments, 8, 29 282 suggestions for access to studies leading L to changes in, 10–11, 110 suggestions for clarifying, 16, 204 Labeling of pediatric medicines suggestions for follow-up safety studies based on extrapolation from adult after changes in, 12, 139 studies, 4, 12–13 time from initiation of study to, 149 biologics, 3, 5, 16–17, 27, 67–68, types of changes in, 197–203 217–218, 220–221, 228, 325–358t types of studies supporting changes in, clarity of changes in, 201–202, 202b, 194, 195t 203 for use with neonates, 144 clinician awareness of changes in, 203, Lamivudine, 172t 274–275 Lamotrigen, 92n contents, 271 Lansoprazole, 159, 162b, 169t current shortcomings, 15, 273 Laronidase, 350t, 367t data sources for analysis of, 5–6, 118, Leflunomide, 119, 196, 198b 119, 178, 262–264 Levalbuterol hydrochloride, 132–133 definition of pediatric age group, 36, 40 Lexi-Comp, 279 Read the entire page →
From page 403... ... 403 INDEX Lindane, 96 National Institutes of Health Linezolid, 171t biologics regulation in, 29–30 Long-term outcomes neonate studies, 14, 163–164, 164t, biologics use, 313 166–167 current shortcomings in pharmaceutical in orphan drug development, 213 research, 2, 7, 26–27, 167 pediatric drug development program data sources, 25 under BPCA, 8–9, 31, 35, 76–77, developmental psychopharmacology 188 considerations, 61 scope of pdiatric research activities, 35, FDA database of postmarket studies, 59–60 147n suggestions for, 14, 166–167 neonatal research, 142, 143, 167 National Library of Medicine, 110 one-year safety reviews, 125–126 National Research Council, 30 required postmarket safety studies, Nelfinavir, 172t 126–127 Nelson's Pocket Book of Pediatric research rationale, 124–125 Antimicrobial Therapy, 279 suggestions for safety studies, 12, 139 Neofax, 278, 279, 281 Lopinavir-ritonavir, 143–144, 156, 171t Neonatal assessment tools, 146 Neonatal medicine analgesia drugs, 143, 146 M assessment tools, 146 challenges of medication testing, Make Medicines Child Size, 36 142–144 Malaria, 213–214 current shortcomings in pharmaceutical MD Consult, 279–280 research, 2, 7, 13, 26–27, 141 MedGuides, 272 deferred studies, 152 Medscape/WebMD/eMedicine, 279 developmental pharmacology, 46 MedWatch, 68 FDA expertise for study assessments, Meropenem, 274–275 162–163, 166 Methadone, 164 gestational age, 142 Methylphenidate, 48, 132b labeling, 153–163, 168–175t Metronidazole, 164–165 long-term investigations, 142, 143, 167 Micafungin, 273 medications commonly used in intensive Micromedex, 279 care, 144–146, 145t Migraine, 121, 182–183, 184b, 198b National Institutes of Health studies, 14, Mometasone furoate, 121, 202b 163–164, 166–167 Monoclonal antibodies, 288–290, 289t, number and origins of studies, 146–149, 292–293, 311 165–166 Monthly Prescribing Reference, 280 outcomes of BPCA studies, 165–167 Moxifloxacin, 157–158, 172t PREA requirements, 151–153 rationale for medication studies, 13–14, 141, 144 N suggestions for improving pharmaceutical research, 3, 14, Natalizumab, 350t, 367t 166–167 National Academy of Sciences, 30 variability within age groups, 142 National Commission for the Protection of waivers from clinical assessment Human Subjects of Biomedical and requirements, 13, 151–153, 151n Behavioral Research, 30–31 written requests under BPCA, 149–151 National Institute of Child Health and Nevirapine, 23b, 170t Human Development, 59, 164–165, 188 Read the entire page →
From page 404... ... 404 INDEX P New Drug Application, 9, 65–67, 98, 114, 151, 188 Palifermin, 351t, 368t pediatric exclusivity program, 70–74 Palivizumab, 352t, 369t priority review, 213 Pancrelipase, 123–124 Newborn Drug Development Initiative, 164 Panitumumab, 352t, 369t Nitric oxide, 119, 149, 168t Pantoprazole, 52, 133, 138–139, 159, 162–163b, 169t Parental consent for child research subjects, O 94 Ofatumumab, 350t, 367t Patient Protection and Affordable Care Act, Office of Good Clinical Practice, 98 24, 34, 207, 261 Office of New Drugs, 97 Pediatric Academic Societies, 59 Office of Pediatric Therapeutics, 83–84, 97, Pediatric Advisory Committee, 25, 84, 96, 274 125, 272 Off-label use Pediatric and Maternal Health Staff, 97 ambiguous labeling, 15–16, 204, Pediatric Labeling Rule, 31 278–279, 280–281 Pediatric Pharmacology and Therapeutics data sources for evaluation of, 19–20, Research Consortium, 59 25 Pediatric plan definition, 40 requirements for, 78–79 ethical issues in, suggested change in requirements for, 9, 20 87 with neonates, 14, 141–142, 144 Pediatric research, generally prevention of, 26 age range definition, 4–5, 36–37, 63 as source of adverse events, 44, 272 benefits, 2, 6, 15, 22–23b, 26 Off-patent products, 35, 76–77, 163, 188 consideration of developmental Ofirmev, 168t variability, 49–58 Ofloxacin, 158, 175t current shortcomings, 2, 6, 15, 26–27 Olmesartan, 120b, 202b economic incentives, 1, 3, 8–9, 19, Omalizumab, 23b, 37, 120b, 122–123, 151, 32–33 198b, 351t, 368t ethical issues in, 10–11 Omeprazole, 159 historical evolution, 19–20, 20t, 29–36, Ondansetron, 152 63 One-year safety reviews, 25, 125–126 legislative mandates, 1, 3, 8, 9, 19, 33 Oprelvekin, 351t, 368t obstacles and disincentives, 4, 21–23, Orphan Drug Act, 3, 9, 16, 27, 34–35, 209, 271 211, 212–213, 228 outside the United States, 35–36, Orphan drugs, 34–35 92–93 biologics, 16, 221 protections for pediatric research efficacy studies, 213 participants, 93–96 European rules, 82–83 rationale, 4, 20–21, 43–44 exclusivity incentives for, 212 risk assessment, 91b, 95–96, 118, neonate studies, 147 121–123 pediatric approvals, 16, 212 salient issues, 1–2, 5, 24–25, 28, postmarket studies, 212 261–262 quality of studies in support of, 213 strategies for improving, 2, 3–4, 15, 19, Osteogenesis imperfecta, 57, 76, 121, 130 32, 204–205, 271–272 Otelixizumab, 311 suggestions for improving, 3 Overweight and obese children, 47 types of studies, 37–39 Oxycodone, 152 See also Neonatal assessment tools Read the entire page →
From page 405... ... 405 INDEX Pediatric Research Equity Act, 62 types of labeling changes made under, age range covered by, 4–5 197–203 approval letters, 188–189, 190 use of extrapolation studies under, 137, Best Pharmaceuticals for Children Act 138t and, 34, 81 waiver of pediatric assessment biologics coverage under, 3, 16, 27, 207, requirements, 80–81, 80t, 189–190 214–215, 228 Pediatric Review Committee, 9–10, 84, 97, clinical reviews, 112–114 115, 189, 194 cost-benefit analysis, 109 Pediatric Rule, 9, 33, 77, 81, 262, 271–272 creation of, 33, 77 biologics coverage under, 214 data sources for analysis of, 112, 189 Pediatric Trials Network, 59 deferral of pediatric assessments, 79, Pegfilgrastim, 196–197, 352t, 369t 189, 190, 191–193, 192t Peginterferon alfa-2a, 212n, 353t, 369t deficiencies resulting in inadequate Peginterferon alfa-2b, 354t, 370t studies, 195–197, 198–199b, 203 Pegloticase, 225b, 354t, 370t effects on clinical practice, 25 Pharmaceutical industry ethical implementation, 89, 99–108 economic incentives for pediatric FDA administrative structure for, 83–84 research, 1, 3, 8–9 labeling changes attributed to, 178 FDA terminology, 41 neonatal assessments under, 141, 148, penalties for delayed studies, 15 151–153, 165–167 percentage of written requests initiated objectives, 1, 19, 77, 111, 271–272 by, 182 one-year safety reviews, 125–126 as source of prescribing information for orphan product exemptions, 212 clinicians, 276 outcomes to date, in pharmaceutical uncertainty arising from reauthorizations safety and effectiveness, 2–3, 6–8, of laws, 3, 7, 27 26–27 See also Exclusivity, pediatric marketing pediatric plan, 78–79 Pharmaceutical research and development primary provisions, 9, 78 additives, 50 proposal for permanent reauthorization, definition of drug, 64 86–87 drug formulation and delivery systems, public access to studies conducted under, 49–52 10–11, 84–86, 100–102, 109, 112, ethical issues in pediatric studies, 10–11 272 evolution of regulatory framework, reauthorizations, 3, 7, 9, 27, 87 29–36 requests for studies of off-patent FDA application and review, 65–67 products, 77 generic drugs, 71n requirements for biologics research, 3, legislative requirements, 9 7–8 obstacles and disincentives to, 4, 21–23 retroactive application, 81 pediatric plan, 78–79 safeguards for pediatric research, 10 pharmacogenetic considerations, 48–49 salient issues in analysis of, 1, 5, 24, 28, postmarket monitoring, 68–70 261–262 product labeling requirements, 67–68 scope and outcomes of requested types of studies for, 37–38 labeling changes, 14–16, 22–23b, 34, See also Neonatal medicine; Pediatric 177–180, 178f, 194, 195t research, generally scope and outcomes of required studies, Pharmacodynamics 2, 188–193, 203 challenges in neonatal research, 142, specifications for types of required 143 studies, 190–191 rationale for pediatric studies, 4, 21 suggestions for improving, 3 Pharmacogenomics, 48–49 Read the entire page →
From page 406... ... 406 INDEX Pharmacokinetics on studies earning exclusivity, 100, 108 approaches to pediatric research, 56–57 suggestions, 3, 10–11, 13, 109–110, 140 biologics data, 292–293 Public Health Service Act, 5, 25, 63, 64, challenges in neonatal research, 142, 207, 208, 286 143 PubMed, 11, 102, 110 cost of studies, 107 Pure Food and Drugs Act, 29 developmental pharmacology, 44–48 disease conditions affecting, 47 Q ethical practice in pediatric studies of, 103–104 Quinidine sulfate, 133 extrapolation from adult studies, 13 genetic variability, 48–49 labeling changes supported by studies of, R 194, 195t rationale for pediatric studies, 4, 21 Rabeprazole, 159 shortcomings of pediatric knowledge Ranibizumab, 224b, 354t, 370t base, 292 Ranitidine, 174t study outcomes to date, 2, 6, 26 Rasburicase, 370t Physicians' Desk Reference, 279 Reauthorizations of BPCA and PREA, 3, 7, Placebo studies, 10, 58, 104–106, 109 9, 27, 33, 86–87 Postmarket monitoring, 68–70 Recombinant-derived therapeutics, public access to information about, 288–290, 291–292t 191–193 Recruitment for research, 2, 4, 21–22, 58, required safety studies, 126–127 59–60, 142, 196–197 Postmarket study commitments, 38 Red Book, The, 279 Pralidoxime chloride, 179 Redaction of FDA documents, 2–3, 6, 7, Premature or low-birthweight infants 10–11, 27, 100, 102, 109–110, 118, chloramphenicol treatment, 43–44 119, 158 current shortcomings in pharmaceutical Regulatory science, 60 research, 2, 7 Remifentanil, 172t, 200b developmental pharmacology, 46–47 Research designs Priority review vouchers, 213–214 acceptance of studies conducted outside Propofol, 198b the United States, 92–93 Protein-based biologics, 210 adaptive designs for pediatric studies, Protein C concentrate, 354t, 377t 57–58 Proton pump inhibitors, 159–161 age-group selection, 55–56 Pseudobulbar effect, 133 biospecimen sampling, 54–55 Pseudophedrine, 152 challenges of medication testing with Psoriasis, 303–305 neonates, 142–144 Public access to information current shortcomings, 2, 6, 15, 26 about abandoned or incomplete studies, developmental considerations, 52, 54–58 101 obstacles to pediatric research, 4, 21–22 biologics applications and reviews, 215 pharmacogenetic considerations in, current requirements for BPCA and 48–49 PREA, 84–86, 100–102, 112 placebo-controlled studies, ethics deferral of pediatric assessments, 79, considerations in, 10, 58, 104–106 191 protection of human research on labeling changes, 100–101, 272, 274 participants, 90–96 redaction of FDA documents, 2–3, 6, 7, randomized withdrawal, 58, 106 10–11, 27, 100, 102, 109–110, 118, strategies for improving, 2, 15, 204–205 119, 158 Read the entire page →
From page 407... ... 407 INDEX written requests for hypertension studies, sources of information on, 112–114 381–385 study outcomes to date, 2, 6, 26 See also Alternative endpoints substantial evidence of, 66–67 Rheumatoid arthritis, 119, 196, 198b, 199b suggestions for long-term follow-up Rho(D) immune globulin intravenous, studies, 12, 139 217–218, 225b, 355t, 378t suggestions for use of template for Ribavirin, 127 clinical reviews, 12, 139 Rickettsia, 43–44 terminology, 39 Rifapentine, 104n types of labeling changes based on, Rilanocept, 356t, 370t 197–203 Rilpivirine, 152 Salmeterol xinafoate, 119–121 RimabotulinumtoxinB, 223b, 356t, 370t Salmonella, 43–44 Risedronate, 76 Sanctions and penalties Risk-benefit assessments for delayed studies, 15, 79 analysis of clinical reviews of pediatric Schizophrenia, 120b, 127, 202b studies, 118, 121–123 Secretary of Department of Health and ethics issues, 90, 91b, 93, 94b, 95–96, Human Services, 5, 24, 70–71 97, 99, 103–104 Sevoflurane, 174t long-term studies, 61 Sipuleucel T, 225b, 356t, 378t structured framework for, 123 Smallpox vaccine, 29 suggestions for, 12, 139 Somatropin recombinant, 65 terminology, 39 Sotalol hydrochloride, 50, 56–57, 122, 149, Rituximab, 309, 312, 356t, 371t 173t, 199b Rocuronium bromide, 154–155b, 155–156, Statins, 61 169t Stavudine, 173t Romiplostim, 223b, 356t, 371t Study Endpoint and Labeling Development Rusbiricase, 355t Group, 130 Substantial evidence of safety and effectiveness, 66–67 S Subtherapeutic dosing, 96 Suggestions for Safety of pediatric medicines, 28 biologics research, 3, 12, 16, 139, 229 analysis of clinical reviews of pediatric clarity of labeling, 16, 204 studies, 117–123 data sources and methodology for biologics, 294–295 development of, 25 clinical trials assessment and monitoring, documentation of ethical practice, 114–115, 117 109 cost of tests for, 107 dosing research, 15, 203 extrapolation from adult studies, 123–124 expanded public access to information, historical evolution of regulatory 3, 10–11, 109–110, 140 framework, 29–36 format and content of safety and efficacy historical evolution of research and studies, 3, 12, 13, 15, 139, 140, 204 labeling, 19–20, 20t improving pediatric studies of drugs and labeling changes supported by studies of, biologics, 15, 205 194, 195t neonatal drug studies, 3, 14, 166–167 national system for ensuring, 111–112 placebo-controlled trials need for long-term studies, 124–125 postmarket follow-up studies, 12, 139 new product application and review, reporting on use of endpoints in 65–67 pediatric studies, 12, 140 one-year reviews, 125–126 timeliness of pediatric studies, 3, 9, 15, quality of FDA studies, 11–12 26, 87 required postmarket studies, 126–127 Read the entire page →
From page 408... ... 408 INDEX Sumatriptan, 184b U.S. Congress, 2–3, 7, 9–10, 27, 33, 34, Surrogate endpoints, 53, 129–130, 130n 84–85, 86, 87, 100, 125, 204, 274 suggestions for, 3, 10–11, 14, 15, 109–110, 166–167, 229 T Ustekinumab, 358t, 372t Tarascon Pharmacopoeia, 279 Telithromycin, 99 V Tenecteplase, 356t, 372t Tenofovir disoproxil fumarate, 119, 122, Vaccines, 29, 215, 264, 285, 322–323 147n, 201b adverse event monitoring, 68–69 Teplizumab, 311–312 Vaccinia immune globulin intravenous, Terbinafine hydrochloride, 51 358t, 378t Thalidomide, 29 Valganciclovir, 52, 102–103, 169t Thrombin, topical, 357t, 378t Vinorelbine tartrate, 200b Timeliness of processes, 2, 6–7, 9, 26 Vitamin E, 142 deferral of PREA studies, 191–193, 192t von Willebrand factor, 358t, 379t European medical research requirements, 82 W FDA capacity to impose sanctions for delayed studies, 15 Waivers FDA determination of exclusivity for neonatal assessment, 13, 151–153, awards, 73 151n FDA requirements, 82 of pediatric assessment requirements, international harmonization of 80–81, 80t regulations, 87 for pediatric formulation, 52 public access to information about, pediatric studies of biologics with, 221, 191–193 222–223b suggestions, 3 rationale under PREA, 189–190 from study initiation to labeling change, Water soluble drugs, 45 149 WebMD, 279 time from written request to completed World Health Organization, 36 review, 87 Tinea capitis, 51 Tocilizumab, 300, 301–302, 357t, 372t X Tositumomab and iodine, 225b, 357t, 372t Trastuzumab, 357t, 372t Xigris, 364t Tropical disease drugs, 213–214 Tumor necrosis factor inhibitors, 294–295 Z U Zidovudine, 177 Zoledronic acid, 57, 202b Ulcerative colitis, 305–308 Zolmitriptan, 184b, 198b Update of the American Academy of Pediatrics, 274 UpToDate, 279–280 Read the entire page →

From page 395...

... , 190, 327t, 372t Adalimumab, 120b, 132b, 151, 201b, Albuterol sulfate, 57, 133 294–295, 300–301, 307, 326t, 360t Alefacept, 327t, 360t Adolescents Alemtuzumab, 327t, 360t developmental pharmacology, 47 Alendronate, 121, 132b in pediatric age range, 47 Alglucosidase alfa, 212, 213, 327–328t, Adults, pediatric drug use based on studies 361t with Almotriptan, 103, 121, 184b analysis of clinical reviews of, 119, 120b Alpha1-proteinase inhibitor, 222b, 224b, extrapolation of safety in, 123–124 328–329t, 372–373t risks in, 4, 30, 273 Alternative endpoints See also Alternative endpoints; composite endpoints as, 53–54 Extrapolation of efficacy definition, 12, 39, 128–129 Adverse Event Reporting System, 68, 272 study goals, 5, 12 Adverse events suggestions for reporting on use of, in data sources, 11–12 studies, 12, 140 definition, 11, 39, 115–117 395

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From page 396...

... v. FDA, 33 public access to studies conducted under, Asthma, 21, 23b, 48, 51, 120b, 121, 3, 11, 84–86, 100–102, 109, 112, 132–133, 198b, 202b 272 Atopic dermatitis, 302–303 reauthorizations, 3, 7, 9, 27, 87 Attention deficit hyperactivity disorder, 48, requests for studies of off-patent 69, 122n, 125, 199b products, 76–77 Autism, 151n safeguards for pediatric research, 10 Autologous cultured chondrocytes, 331t, salient issues in analysis of, 1, 5, 24, 28, 374t 261–262 Azithromycin, 164 scope and outcomes of studies under, 2, 14–16, 22b, 23b, 34, 74–76, 177–183, 178f, 182f, 203 B sources of requests, 182, 226 strategies for improving, 3, 166–167 Basilixmab, 332t, 361t suggestions for neonatal assessments Becaplermin, 224b, 226, 227, 332t, 361t under, 14, 166–167 Belmont Report, 30–31 types of labeling changes made under, Benzyl alcohol, 30 197–203 Besifloxacin ophthalmic, 158–159 Betamethasone, 164 Best Pharmaceuticals for Children Act Better Pharmaceutical for Children, 32 age range covered by, 4–5 Bevacizumab, 309, 332t, 362t biologics coverage added, 3, 7–8, 16, 27, Biologics 34, 207 access to application and review data, biologics with possible promise for 215 pediatric study, 226 approval letters, 218 clinical reviews, 112–114

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From page 397...

... 397 INDEX biosimilarity and interchangeability, See also Biologics License Application; 208–209 Center for Biologics Evaluation and clinical pharmacology, 292–293 Research; Vaccines clinical trials registry, 219–220, Biologics Control Act, 29, 285 359–379t Biologics License Application, 9, 65–66, current pediatric labeling, 3, 16–17, 27, 114, 151, 188, 209 217–218, 220–221, 228 priority review, 213 data sources for analysis of pediatric supplemental, 209 research, 6, 178, 215–220, 263, Biologics Price Competition and Innovation 321–324 Act, 2, 5, 24, 63, 207, 208–211, definition, 7n, 64–65, 208n, 210, 286 214–215, 228–229, 262 developmental pharmacology, 313 Biosimilar products, 208–209 extension of BPCA to, 3, 16, 27, 34, 63, Biospecimen sampling, 54–55 207, 208–215 Bipolar disorder, 127 future prospects, 17, 228–229 Bivalirudin, 174t, 180 historical and technical evolution, Botulism immune globulin, 41, 333t, 374t 285–286 Bronchopulmonary dysplasia, 119, 129, 149 labeling information on FDA-approved Buspirone hydrochloride, 132b, 138, 202b products, 220–221, 325–358t labeling requirements, 67–68 C market exclusivity protections for, 71–73, 207, 209, 210, 211, 228 C1 esterase inhibitor, 333t, 374t mechanism of action, 290 Caffeine citrate, 144–145 neonate studies, 146–147 California Department of Health Services, Orphan Drug Act and, 34, 78, 212–213, 41 228 Canakinumab, 334t, 363t outcomes to date of legislative Cancer, 308–310, 312–313 requirements for research on, 3, 7–8, Candesartan, 201b 27 Candidiasis, 273 plasma-derived, 287–288, 288t, 293, Caspofungin, 170t 294 Ceftaroline fosamil, 152 PREA requirements for, 7, 16, 33, 78, Ceftriaxone, 143 207, 214–215, 222–223b Center for Biologics Evaluation and priority review vouchers, 213–214 Research, 29–30, 83, 84, 97, 112, products not tested for pediatric use, 5, 114, 180, 193, 216, 286 215, 222–226, 224–225b suggestions for, 12, 139 products studied with children, 7–8, 27, Center for Devices and Radiological Health, 220–221, 221t, 359–379t 97 products with possible promise for Center for Drug Evaluation and Research, pediatric study, 226–227, 228 12, 83, 84, 97, 112–114, 115, 128, recombinant-derived, 288–290, 130, 180, 193, 286 291–292t Certolizumab pegol, 334t, 363t safety concerns, 294–295 Cetuximab, 309, 334t, 363t salient issues in pediatric medicine, 1, 2, Children's Health Act, 93, 309 5, 24–25, 207–208, 262 Children's Oncology Group, 59, 196–197 sources of, 286–287 Chloramphenicol, 43–44, 90, 141 structure, 287, 287f Ciprofloxacin, 158, 174t suggestions for research, 3, 16, 229 Cisapride, 101 supplemental license applications, 209 Clinical and Translational Science Awards, therapeutic applications, 296–313 59 types of, 287–290

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From page 398...

... 398 INDEX Clinical practice, 25, 39 support infrastructure for pediatric clinician awareness of labeling changes, research, 58–60 274–275 trial design, 56–58 sources of prescribing information, types of, 38b 276–281, 277–278t, 281t, 282 See also ClinicalTrials.gov Clinical reviews by FDA ClinicalTrials.gov, 11, 85, 102, 110, 219, analysis of efficacy assessments in, 323 131–133 Clopidogrel, 58, 149, 154b analysis of safety assessments in, 11, Coagulation factor IX, 335t, 375t 117–123 Coagulation factor VIIa, 335t, 374t audience, 113–114 Collagenase clostridium histolyticum, 225b, as data source, 112–113 335t, 363t definition, 112–113 Composite endpoints, 53–54 description of endpoints in, 12, Confidentiality and privacy 131–133, 194 protections for research subjects, 90 description of research design and redactions in clinical reviews to protect, integrity in, 10, 100, 102–103, 109 193 discussion of developmental variability, Conflict of interest, 90, 102 194 Conjunctivitis, 101, 147, 153, 157–159 effects on labeling, 118, 119 Corticosteroids, 48 efficacy review template, 128, 129b Cost-benefit analysis of BPCA and PREA, justification for use of extrapolation of 109 efficacy in, 13, 134–136 Creating Hope Act, 213 public access to, 13, 109, 112 Crohn's disease, 305–308 quality of, 112, 114, 139, 193–194 Crotalidae polyvalent immune Fab, 217, redacted material, 10–11, 100, 102, 336t, 375t 109–110, 118, 119, 158, 193 Cystic fibrosis, 35 safety review template, 12, 115, 116b, Cystic Fibrosis Foundation, 60 139, 193 Cystic Fibrosis Therapeutic Development scope of, 113 Network, 60 sources of, 112 Cytochrome enzymes, 45, 46 suggestions for, 10, 12, 139 Cytomegalovirus, 103 template for reviews, 113b Clinical trials D abandoned, 101 conducted outside the United States, Daclizumab, 336t, 364t 92–93 Darbepoetin, 337t, 364t data integrity, 91 Darunavir, 150 database, 219n Data monitoring committee, 114–115 definition, 37–38 Declaration of Helsinki, 92, 104 drug delivery documentation, 51 Denileukin diftitox, 337t, 364t ethical issues in, 10 Denosumab, 337t, 364t limits of short-term studies, 61 Department of Health and Human Services, for pediatric populations, 55–56 90, 93 pharmacogenetic considerations in, Desflurane, 120b, 128, 200b, 203 48–49 Developmental pharmacology protection of research participants, of biologics, 313 90–96 consideration of, in FDA reviews, 194 registry, 219–220, 359–379t implications for drug formulation and safety assessment and monitoring in, delivery, 49–52 114–115, 117

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From page 399...

... 399 INDEX implications for pediatric research labeling changes supported by studies of, design, 54–58 194, 195t long-term use of drugs, 61 national system for ensuring, 111–112 pharmacogenetic factors, 48–49 new product application and review, research support infrastructure for 65–67 consideration of, 58–60 orphan drug studies, 213 in selection of endpoint measures, 52–54 salient issues in analysis of, 28, significance of, 44–48, 49 127–128, 261 Dextromethorphan hydrobromide, 133 sources of information on, 112–114 Diabetes, 22b, 310–312, 313 study outcomes to date, 2, 6, 26 Didanosine, 156, 173t template for, 128, 129b Diethylene glycol, 29 terminology, 39 Difluprednate ophthalmic solution, 147n types of labeling changes based on, Digoxin immune Fab, 338t, 375t 197–203 Diphtheria antitoxin, 29 See also Alternative endpoints; Division of Scientific Investigations, 98, 102 Endpoints, primary efficacy; Dosing Extrapolation of efficacy clinician access to new information on, Eletriptan, 184b 274 Elimination, drug, 45–47 developmental pharmacology, 46 Elixir Sulfanilamide, 29 extrapolation of pediatric dose from Emphysema, 222b adult studies, 4, 273, 273t eMPR, 280 label guidelines for off-label pediatric Emtricitabine, 155b, 171t use, 15–16, 204 Endpoints, primary efficacy, 12, 15, 39, sources of prescribing information 131–133. See also Alternative for pediatric clinicians, 276–281, endpoints 277–278t, 281t, 282 Epocrates, 279 subtherapeutic, 96 Esomeprazole magnesium, 122, 159, 163b, suggestions for pediatric research, 15, 169t 203 Etanercept, 294–295, 300, 304–305, 339t, See also Developmental pharmacology 365t Drotrecogin alfa, 338t Ethical issues Drug Facts and Comparisons, 279 acceptance of studies conducted outside Drugs, definition of, 64 the United States, 92–93 Drugs@FDA, 100, 274 in BPCA implementation, 89, 99–108 challenges in pediatric research, 22–23 clinical trial safeguards, 10 E current state of pediatric research, 108–109 Ecallantide, 339t, 364t FDA resources to support, 96–99 Eculizumab, 339t FDA reviewer comments on, 102–103 Effectiveness of medical intervention, 39 historical evolution of pediatric research, substantial evidence of, 66–67 30–31 Efficacy of pediatric medicines intergenerational justice, 11, 107 assessment of FDA reviews, 131–133 marketing exclusivity and, 11, 107–108 cost of tests for, 107 in medication testing with neonates, 142 FDA requests for studies of, 128 need for safety and efficacy studies for, historical evolution of regulatory 20 framework, 29–30 in pharmacokinetic studies, 103–104 historical evolution of research and in placebo-controlled studies, 10, labeling, 19–20, 20t 104–106, 109

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From page 400...

... 400 INDEX in PREA implementation, 89, 99–108 extent and patterns of use, 12–13, principles of pediatric drug studies, 89 137–139, 137t, 138t, 140 protection of research participants, FDA allowance for use of, 31, 56, 90–96 133–135 restrictions on medical research, 10 limitations, 273 suggestions for documentation of, 10, options, 136–137 109 partial, 136–137n Etodolac, 199b rationale, 134 Europe, research policies in study goals, 5, 12, regulatory authority, 80–83 24 timelines for pediatric studies, 2, 6–7, 9, suggestions for FDA public reports on 26, 36, 82 acceptance of, 13, 140 See also International harmonization of Extrapolation of safety, 123–124 research policies Exulizumab, 365t European Medicines Agency, 9, 36, 79 Food and Drug Administration and, F 81–83 Evidence-based practice, 20 Factor XIII concentrate, 212 Exclusivity, pediatric marketing Famotidine, 173t approval rate for, 14 Federal Food, Drug, and Cosmetic Act, 5, based on active moiety, 74, 76 25, 29, 30, 63, 64, 286 biologics coverage, 16, 207, 209, 210, Fenoldopam, 149, 172t 211, 228 Fentanyl, 153 duration, 209 Fibrin sealant, 339–340t, 375t eligible products, 74 Fibrinogen, 376t ethical concerns, 11, 107–108 Fibrinogen concentrate, 341t European approach, 81–82 Fluconazole, 180, 273 FDA guidance, 33 Fluticasone propionate, 119–121, 199b frequency and outcomes of requests for, Food and Drug Administration 180–181, 182t acceptance of extrapolated data in legislative basis, 8–9, 32, 70 efficacy studies, 31, 56, 133–135 objectives, 71 acceptance of studies conducted outside Pediatric Research Equity Act and, 81 the United States, 92–93 potential value of, 33, 107 advancement of regulatory science, public access to requests and reviews 60 relating to, 100, 108 adverse events data, 11–12, 115–118 requirements for, 70–71, 73 articulation of expected health benefits scope of, 8, 32–33, 72–73, 76 of requested studies, 15, 204 second award, 74n authorities and responsibilities, 4, 19, timeliness of FDA determination, 73 34–35, 111, 286 under Orphan Drug Act, 212 basic regulatory framework, 64–70 without labeling changes, 108, 179–181 capacity to impose sanctions for delayed Expertise in neonatal research and care, studies, 15 162–163, 166, 187 data sources for analysis of pediatric Extemporaneous formulation, 50 research, 5–6, 189, 262–265 Extrapolation of efficacy database of postmarket studies, 147n decision tree for use of, 134, 135f definition of pediatric age group, 36–37, definition, 39–40 63 description of justification for use of, documentation of research practices, 10 in requests and clinical reviews, European Medicines Agency and, 81–83 134–136, 140

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From page 401...

... 401 INDEX evolution of pediatric drug research, Gatifloxacin ophthalmic, 122, 157, 158, 29–35 174t, 180 international harmonization of research General Guidelines for the Evaluation policies, 36, 87 of Drugs to Be Approved for Use new drug application and review, 65–66 During Pregnancy and for Treatment percentage of written requests initiated of Infants and Children, 30 by, 182 Generic drugs, 71n postmarket surveillance requirements, Golimumab, 341t, 365t 68–70 Government Accountability Office, 109 protections for human research Griseofulvin, 115n participants, 90–96, 91b Guanfacine, 69, 122n, 199b requests for studies of off-patent products, 76–77 H requirements for long-term studies, 61 resources in support of ethical standards Harriet Lane Handbook, The, 274, 276, in research, 96–99 279, 281 suggestions for, 3, 10–11, 12, 13, 15, Hemangiomas, infantile, 17, 226, 227 109–110, 139, 140, 203, 204, 205 Hemophilia, 294, 296–297 See also Best Pharmaceuticals for Hepatitis B immune globulin intravenous, Children Act; Center for Biologics 342t, 376t Evaluation and Research; Center Hepatitis C virus, 22–23b, 127, 212n for Drug Evaluation and Research; Hepatoblastoma, 143 Clinical reviews by FDA; Pediatric HIV infection, 23b, 48, 150, 156–157, 201b Research Equity Act; Pediatric Rule Human growth hormone, 65 Food and Drug Administration Amendment Human Subject Protection/Bioresearch Act, 24, 52, 69, 123, 180, 207, 213 Monitoring Council, 98 Food and Drug Administration Hyaluronidase recombinant human, 65 Modernization and Accountability Hydrochlorothiazide, 164 Act, 8, 20, 32, 66, 70, 218n, 271 Hydrocodone, 152 Food and Drug Administration Safety and Hydrocortisone butyrate, 132b Innovation Act, 64n Hydroxyethyl starch, 147n, 155b, 171t Forced expiratory volume measurement, 53, Hypertension, 120b, 182–183, 185, 201b 131–133 written requests for studies, 381–385 Foreign research, 35–36. See also Europe, research policies in Formulations for pediatric administration, I 49–52 rationale for pediatric studies, 4, 21 Ibritumomab, 342t, 365t Foundation for the National Institutes of Idursulfase, 343t, 366t Health, 77, 163, 188 Immune deficiency syndromes, 298 Freedom of Information Act requests, 100 Immune globulin Fusion proteins, 289, 289t, 290 injection, 344t, 377t intravenous, 217–218, 219, 220, 220n, 225b, 278–279, 294, 298, 345–346t, G 347t, 376t, 377t subcutaneous, 346–347t, 377t Gabapentin, 22b types of, 292 Galsulfase, 341t, 365t See also Monoclonal antibodies Gastroesophageal reflux disease, 133, Immune thrombocytopenic purpura, 299 159–161, 182–183 Incobotulinumtoxin A, 224b, 347t, 366t

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From page 402...

... 402 INDEX Indication for use, 40 effect of clinical reviews, 118, 119 Inflammatory bowel disease, 305–308 evolution of regulatory framework, 29, Infliximab, 294–295, 302, 305, 306–307, 180 348t, 366t exclusivity without changes in, 108, Informed consent, 94 179–181 Inhalants, 51 FDA requirements, 40, 67–68 Institutional review boards, 90, 93, 95, 98 format change, 16, 202–203, 204 Insulin, 65 historical evolution, 19–21, 20t, 31–32 Insulin glargine, 65 indications for use, 40 Insulin glulisine, 22b limitations of legislative requirements, Interchangeability of products, 208–209, 273 220n need for long-term safety studies, Interferon, 22–23b, 127 124–125 Interferon alfacon-1, 225b, 349t, 366t off-label use, 15–16, 204, 278–279, Interferon beta-1a, 349t, 366t 280–281 Interferon gamma-1b, 349t, 367t one-year safety reviews after changes in, Intergenerational justice, 11, 107 125–126 International harmonization of research outcomes of legislation to date, 2–3, 27 policies, 9, 36, 76, 92 outcomes of neonatal assessments, 13, Investigational New Drug application, 65, 146–148, 153–163, 157t, 168–175t 90, 215 pharmacogenetic information, 48–49 Irinotecan hydrochloride, 121, 127, 202b public access to information regarding, 100–101, 272, 274 published literature inconsistent with, J 101 regulatory definition, 40 Juvenile idiopathic arthritis, 55, 120b, salient issues in safety and efficacy 201b, 299–302 analysis, 5, 24 scope and outcomes of requested changes in, 14–16, 34, 177–180, K 178f sources of prescribing information for Kawasaki disease, 298–299 clinicians, 276–281, 277–278t, 281t, Kefauver-Harris Amendments, 8, 29 282 suggestions for access to studies leading L to changes in, 10–11, 110 suggestions for clarifying, 16, 204 Labeling of pediatric medicines suggestions for follow-up safety studies based on extrapolation from adult after changes in, 12, 139 studies, 4, 12–13 time from initiation of study to, 149 biologics, 3, 5, 16–17, 27, 67–68, types of changes in, 197–203 217–218, 220–221, 228, 325–358t types of studies supporting changes in, clarity of changes in, 201–202, 202b, 194, 195t 203 for use with neonates, 144 clinician awareness of changes in, 203, Lamivudine, 172t 274–275 Lamotrigen, 92n contents, 271 Lansoprazole, 159, 162b, 169t current shortcomings, 15, 273 Laronidase, 350t, 367t data sources for analysis of, 5–6, 118, Leflunomide, 119, 196, 198b 119, 178, 262–264 Levalbuterol hydrochloride, 132–133 definition of pediatric age group, 36, 40 Lexi-Comp, 279

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From page 403...

... 403 INDEX Lindane, 96 National Institutes of Health Linezolid, 171t biologics regulation in, 29–30 Long-term outcomes neonate studies, 14, 163–164, 164t, biologics use, 313 166–167 current shortcomings in pharmaceutical in orphan drug development, 213 research, 2, 7, 26–27, 167 pediatric drug development program data sources, 25 under BPCA, 8–9, 31, 35, 76–77, developmental psychopharmacology 188 considerations, 61 scope of pdiatric research activities, 35, FDA database of postmarket studies, 59–60 147n suggestions for, 14, 166–167 neonatal research, 142, 143, 167 National Library of Medicine, 110 one-year safety reviews, 125–126 National Research Council, 30 required postmarket safety studies, Nelfinavir, 172t 126–127 Nelson's Pocket Book of Pediatric research rationale, 124–125 Antimicrobial Therapy, 279 suggestions for safety studies, 12, 139 Neofax, 278, 279, 281 Lopinavir-ritonavir, 143–144, 156, 171t Neonatal assessment tools, 146 Neonatal medicine analgesia drugs, 143, 146 M assessment tools, 146 challenges of medication testing, Make Medicines Child Size, 36 142–144 Malaria, 213–214 current shortcomings in pharmaceutical MD Consult, 279–280 research, 2, 7, 13, 26–27, 141 MedGuides, 272 deferred studies, 152 Medscape/WebMD/eMedicine, 279 developmental pharmacology, 46 MedWatch, 68 FDA expertise for study assessments, Meropenem, 274–275 162–163, 166 Methadone, 164 gestational age, 142 Methylphenidate, 48, 132b labeling, 153–163, 168–175t Metronidazole, 164–165 long-term investigations, 142, 143, 167 Micafungin, 273 medications commonly used in intensive Micromedex, 279 care, 144–146, 145t Migraine, 121, 182–183, 184b, 198b National Institutes of Health studies, 14, Mometasone furoate, 121, 202b 163–164, 166–167 Monoclonal antibodies, 288–290, 289t, number and origins of studies, 146–149, 292–293, 311 165–166 Monthly Prescribing Reference, 280 outcomes of BPCA studies, 165–167 Moxifloxacin, 157–158, 172t PREA requirements, 151–153 rationale for medication studies, 13–14, 141, 144 N suggestions for improving pharmaceutical research, 3, 14, Natalizumab, 350t, 367t 166–167 National Academy of Sciences, 30 variability within age groups, 142 National Commission for the Protection of waivers from clinical assessment Human Subjects of Biomedical and requirements, 13, 151–153, 151n Behavioral Research, 30–31 written requests under BPCA, 149–151 National Institute of Child Health and Nevirapine, 23b, 170t Human Development, 59, 164–165, 188

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From page 404...

... 404 INDEX P New Drug Application, 9, 65–67, 98, 114, 151, 188 Palifermin, 351t, 368t pediatric exclusivity program, 70–74 Palivizumab, 352t, 369t priority review, 213 Pancrelipase, 123–124 Newborn Drug Development Initiative, 164 Panitumumab, 352t, 369t Nitric oxide, 119, 149, 168t Pantoprazole, 52, 133, 138–139, 159, 162–163b, 169t Parental consent for child research subjects, O 94 Ofatumumab, 350t, 367t Patient Protection and Affordable Care Act, Office of Good Clinical Practice, 98 24, 34, 207, 261 Office of New Drugs, 97 Pediatric Academic Societies, 59 Office of Pediatric Therapeutics, 83–84, 97, Pediatric Advisory Committee, 25, 84, 96, 274 125, 272 Off-label use Pediatric and Maternal Health Staff, 97 ambiguous labeling, 15–16, 204, Pediatric Labeling Rule, 31 278–279, 280–281 Pediatric Pharmacology and Therapeutics data sources for evaluation of, 19–20, Research Consortium, 59 25 Pediatric plan definition, 40 requirements for, 78–79 ethical issues in, suggested change in requirements for, 9, 20 87 with neonates, 14, 141–142, 144 Pediatric research, generally prevention of, 26 age range definition, 4–5, 36–37, 63 as source of adverse events, 44, 272 benefits, 2, 6, 15, 22–23b, 26 Off-patent products, 35, 76–77, 163, 188 consideration of developmental Ofirmev, 168t variability, 49–58 Ofloxacin, 158, 175t current shortcomings, 2, 6, 15, 26–27 Olmesartan, 120b, 202b economic incentives, 1, 3, 8–9, 19, Omalizumab, 23b, 37, 120b, 122–123, 151, 32–33 198b, 351t, 368t ethical issues in, 10–11 Omeprazole, 159 historical evolution, 19–20, 20t, 29–36, Ondansetron, 152 63 One-year safety reviews, 25, 125–126 legislative mandates, 1, 3, 8, 9, 19, 33 Oprelvekin, 351t, 368t obstacles and disincentives, 4, 21–23, Orphan Drug Act, 3, 9, 16, 27, 34–35, 209, 271 211, 212–213, 228 outside the United States, 35–36, Orphan drugs, 34–35 92–93 biologics, 16, 221 protections for pediatric research efficacy studies, 213 participants, 93–96 European rules, 82–83 rationale, 4, 20–21, 43–44 exclusivity incentives for, 212 risk assessment, 91b, 95–96, 118, neonate studies, 147 121–123 pediatric approvals, 16, 212 salient issues, 1–2, 5, 24–25, 28, postmarket studies, 212 261–262 quality of studies in support of, 213 strategies for improving, 2, 3–4, 15, 19, Osteogenesis imperfecta, 57, 76, 121, 130 32, 204–205, 271–272 Otelixizumab, 311 suggestions for improving, 3 Overweight and obese children, 47 types of studies, 37–39 Oxycodone, 152 See also Neonatal assessment tools

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From page 405...

... 405 INDEX Pediatric Research Equity Act, 62 types of labeling changes made under, age range covered by, 4–5 197–203 approval letters, 188–189, 190 use of extrapolation studies under, 137, Best Pharmaceuticals for Children Act 138t and, 34, 81 waiver of pediatric assessment biologics coverage under, 3, 16, 27, 207, requirements, 80–81, 80t, 189–190 214–215, 228 Pediatric Review Committee, 9–10, 84, 97, clinical reviews, 112–114 115, 189, 194 cost-benefit analysis, 109 Pediatric Rule, 9, 33, 77, 81, 262, 271–272 creation of, 33, 77 biologics coverage under, 214 data sources for analysis of, 112, 189 Pediatric Trials Network, 59 deferral of pediatric assessments, 79, Pegfilgrastim, 196–197, 352t, 369t 189, 190, 191–193, 192t Peginterferon alfa-2a, 212n, 353t, 369t deficiencies resulting in inadequate Peginterferon alfa-2b, 354t, 370t studies, 195–197, 198–199b, 203 Pegloticase, 225b, 354t, 370t effects on clinical practice, 25 Pharmaceutical industry ethical implementation, 89, 99–108 economic incentives for pediatric FDA administrative structure for, 83–84 research, 1, 3, 8–9 labeling changes attributed to, 178 FDA terminology, 41 neonatal assessments under, 141, 148, penalties for delayed studies, 15 151–153, 165–167 percentage of written requests initiated objectives, 1, 19, 77, 111, 271–272 by, 182 one-year safety reviews, 125–126 as source of prescribing information for orphan product exemptions, 212 clinicians, 276 outcomes to date, in pharmaceutical uncertainty arising from reauthorizations safety and effectiveness, 2–3, 6–8, of laws, 3, 7, 27 26–27 See also Exclusivity, pediatric marketing pediatric plan, 78–79 Pharmaceutical research and development primary provisions, 9, 78 additives, 50 proposal for permanent reauthorization, definition of drug, 64 86–87 drug formulation and delivery systems, public access to studies conducted under, 49–52 10–11, 84–86, 100–102, 109, 112, ethical issues in pediatric studies, 10–11 272 evolution of regulatory framework, reauthorizations, 3, 7, 9, 27, 87 29–36 requests for studies of off-patent FDA application and review, 65–67 products, 77 generic drugs, 71n requirements for biologics research, 3, legislative requirements, 9 7–8 obstacles and disincentives to, 4, 21–23 retroactive application, 81 pediatric plan, 78–79 safeguards for pediatric research, 10 pharmacogenetic considerations, 48–49 salient issues in analysis of, 1, 5, 24, 28, postmarket monitoring, 68–70 261–262 product labeling requirements, 67–68 scope and outcomes of requested types of studies for, 37–38 labeling changes, 14–16, 22–23b, 34, See also Neonatal medicine; Pediatric 177–180, 178f, 194, 195t research, generally scope and outcomes of required studies, Pharmacodynamics 2, 188–193, 203 challenges in neonatal research, 142, specifications for types of required 143 studies, 190–191 rationale for pediatric studies, 4, 21 suggestions for improving, 3 Pharmacogenomics, 48–49

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From page 406...

... 406 INDEX Pharmacokinetics on studies earning exclusivity, 100, 108 approaches to pediatric research, 56–57 suggestions, 3, 10–11, 13, 109–110, 140 biologics data, 292–293 Public Health Service Act, 5, 25, 63, 64, challenges in neonatal research, 142, 207, 208, 286 143 PubMed, 11, 102, 110 cost of studies, 107 Pure Food and Drugs Act, 29 developmental pharmacology, 44–48 disease conditions affecting, 47 Q ethical practice in pediatric studies of, 103–104 Quinidine sulfate, 133 extrapolation from adult studies, 13 genetic variability, 48–49 labeling changes supported by studies of, R 194, 195t rationale for pediatric studies, 4, 21 Rabeprazole, 159 shortcomings of pediatric knowledge Ranibizumab, 224b, 354t, 370t base, 292 Ranitidine, 174t study outcomes to date, 2, 6, 26 Rasburicase, 370t Physicians' Desk Reference, 279 Reauthorizations of BPCA and PREA, 3, 7, Placebo studies, 10, 58, 104–106, 109 9, 27, 33, 86–87 Postmarket monitoring, 68–70 Recombinant-derived therapeutics, public access to information about, 288–290, 291–292t 191–193 Recruitment for research, 2, 4, 21–22, 58, required safety studies, 126–127 59–60, 142, 196–197 Postmarket study commitments, 38 Red Book, The, 279 Pralidoxime chloride, 179 Redaction of FDA documents, 2–3, 6, 7, Premature or low-birthweight infants 10–11, 27, 100, 102, 109–110, 118, chloramphenicol treatment, 43–44 119, 158 current shortcomings in pharmaceutical Regulatory science, 60 research, 2, 7 Remifentanil, 172t, 200b developmental pharmacology, 46–47 Research designs Priority review vouchers, 213–214 acceptance of studies conducted outside Propofol, 198b the United States, 92–93 Protein-based biologics, 210 adaptive designs for pediatric studies, Protein C concentrate, 354t, 377t 57–58 Proton pump inhibitors, 159–161 age-group selection, 55–56 Pseudobulbar effect, 133 biospecimen sampling, 54–55 Pseudophedrine, 152 challenges of medication testing with Psoriasis, 303–305 neonates, 142–144 Public access to information current shortcomings, 2, 6, 15, 26 about abandoned or incomplete studies, developmental considerations, 52, 54–58 101 obstacles to pediatric research, 4, 21–22 biologics applications and reviews, 215 pharmacogenetic considerations in, current requirements for BPCA and 48–49 PREA, 84–86, 100–102, 112 placebo-controlled studies, ethics deferral of pediatric assessments, 79, considerations in, 10, 58, 104–106 191 protection of human research on labeling changes, 100–101, 272, 274 participants, 90–96 redaction of FDA documents, 2–3, 6, 7, randomized withdrawal, 58, 106 10–11, 27, 100, 102, 109–110, 118, strategies for improving, 2, 15, 204–205 119, 158

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From page 407...

... 407 INDEX written requests for hypertension studies, sources of information on, 112–114 381–385 study outcomes to date, 2, 6, 26 See also Alternative endpoints substantial evidence of, 66–67 Rheumatoid arthritis, 119, 196, 198b, 199b suggestions for long-term follow-up Rho(D) immune globulin intravenous, studies, 12, 139 217–218, 225b, 355t, 378t suggestions for use of template for Ribavirin, 127 clinical reviews, 12, 139 Rickettsia, 43–44 terminology, 39 Rifapentine, 104n types of labeling changes based on, Rilanocept, 356t, 370t 197–203 Rilpivirine, 152 Salmeterol xinafoate, 119–121 RimabotulinumtoxinB, 223b, 356t, 370t Salmonella, 43–44 Risedronate, 76 Sanctions and penalties Risk-benefit assessments for delayed studies, 15, 79 analysis of clinical reviews of pediatric Schizophrenia, 120b, 127, 202b studies, 118, 121–123 Secretary of Department of Health and ethics issues, 90, 91b, 93, 94b, 95–96, Human Services, 5, 24, 70–71 97, 99, 103–104 Sevoflurane, 174t long-term studies, 61 Sipuleucel T, 225b, 356t, 378t structured framework for, 123 Smallpox vaccine, 29 suggestions for, 12, 139 Somatropin recombinant, 65 terminology, 39 Sotalol hydrochloride, 50, 56–57, 122, 149, Rituximab, 309, 312, 356t, 371t 173t, 199b Rocuronium bromide, 154–155b, 155–156, Statins, 61 169t Stavudine, 173t Romiplostim, 223b, 356t, 371t Study Endpoint and Labeling Development Rusbiricase, 355t Group, 130 Substantial evidence of safety and effectiveness, 66–67 S Subtherapeutic dosing, 96 Suggestions for Safety of pediatric medicines, 28 biologics research, 3, 12, 16, 139, 229 analysis of clinical reviews of pediatric clarity of labeling, 16, 204 studies, 117–123 data sources and methodology for biologics, 294–295 development of, 25 clinical trials assessment and monitoring, documentation of ethical practice, 114–115, 117 109 cost of tests for, 107 dosing research, 15, 203 extrapolation from adult studies, 123–124 expanded public access to information, historical evolution of regulatory 3, 10–11, 109–110, 140 framework, 29–36 format and content of safety and efficacy historical evolution of research and studies, 3, 12, 13, 15, 139, 140, 204 labeling, 19–20, 20t improving pediatric studies of drugs and labeling changes supported by studies of, biologics, 15, 205 194, 195t neonatal drug studies, 3, 14, 166–167 national system for ensuring, 111–112 placebo-controlled trials need for long-term studies, 124–125 postmarket follow-up studies, 12, 139 new product application and review, reporting on use of endpoints in 65–67 pediatric studies, 12, 140 one-year reviews, 125–126 timeliness of pediatric studies, 3, 9, 15, quality of FDA studies, 11–12 26, 87 required postmarket studies, 126–127

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From page 408...

... 408 INDEX Sumatriptan, 184b U.S. Congress, 2–3, 7, 9–10, 27, 33, 34, Surrogate endpoints, 53, 129–130, 130n 84–85, 86, 87, 100, 125, 204, 274 suggestions for, 3, 10–11, 14, 15, 109–110, 166–167, 229 T Ustekinumab, 358t, 372t Tarascon Pharmacopoeia, 279 Telithromycin, 99 V Tenecteplase, 356t, 372t Tenofovir disoproxil fumarate, 119, 122, Vaccines, 29, 215, 264, 285, 322–323 147n, 201b adverse event monitoring, 68–69 Teplizumab, 311–312 Vaccinia immune globulin intravenous, Terbinafine hydrochloride, 51 358t, 378t Thalidomide, 29 Valganciclovir, 52, 102–103, 169t Thrombin, topical, 357t, 378t Vinorelbine tartrate, 200b Timeliness of processes, 2, 6–7, 9, 26 Vitamin E, 142 deferral of PREA studies, 191–193, 192t von Willebrand factor, 358t, 379t European medical research requirements, 82 W FDA capacity to impose sanctions for delayed studies, 15 Waivers FDA determination of exclusivity for neonatal assessment, 13, 151–153, awards, 73 151n FDA requirements, 82 of pediatric assessment requirements, international harmonization of 80–81, 80t regulations, 87 for pediatric formulation, 52 public access to information about, pediatric studies of biologics with, 221, 191–193 222–223b suggestions, 3 rationale under PREA, 189–190 from study initiation to labeling change, Water soluble drugs, 45 149 WebMD, 279 time from written request to completed World Health Organization, 36 review, 87 Tinea capitis, 51 Tocilizumab, 300, 301–302, 357t, 372t X Tositumomab and iodine, 225b, 357t, 372t Trastuzumab, 357t, 372t Xigris, 364t Tropical disease drugs, 213–214 Tumor necrosis factor inhibitors, 294–295 Z U Zidovudine, 177 Zoledronic acid, 57, 202b Ulcerative colitis, 305–308 Zolmitriptan, 184b, 198b Update of the American Academy of Pediatrics, 274 UpToDate, 279–280

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Index Pages 395-408

Index
Pages 395-408