Index

A

Abbreviated New Drug Application (ANDA), 76, 89, 93

AbioCor Implantable Replacement Heart, 218 n.12, 221

Abiomed, 218 n.12

Acceleration of discovery research

(see also Integrated national strategy)

advocacy group approaches, 371-386

barriers to, 18

biomarkers as surrogate endpoints and, 8

opportunities for, 6-7

patient registries and, 8

task force on, 14, 242, 247-248

Access to orphan drugs

(see also Coverage and reimbursement)

advocacy groups and, 83 n.4, 200

company assistance programs, 83 n.4, 198-200

Acetylation, 116, 117, 345, 357

Achondrogenesis type 1A, 127

Acne rosacea, 318

Acromegaly, 45 n.3, 328, 330

Activa Dystonia Therapy, 221

Acute hyperammonemia, 96

Acute intermittent porphyria, 368

Acute lymphoblastic leukemia, 298-299, 329, 330, 338, 339

Acute lymphocytic leukemia, 48 n.5

Acute myeloid leukemia, 48 n.5, 131

Acute promyelocytic leukemia, 325

Acute respiratory distress syndrome (adult), 131

Adalimumab (Humira), 304 n.31, 340, 42

Adenocarcinoma salivary duct carcinoma, 369

Adenoid cystic carcinoma, 369

Adenosine deaminase deficiency, 300 n.20

Advanced Medical Technology Association, 237-238

Advanced Research Collaboration model, 127, 141, 371

Advancing Regulatory Science Initiative, 102, 103

Advocacy groups

(see also specific groups)

activities of, 2, 21, 28, 29, 70, 71

consolidation of, 70-71

educating clinicians, 66

research strategies, 71-72, 137-138, 168, 371-386

resource differences, 372-373

Aetna, 225

Agency for Healthcare Research and Quality, 10, 133, 193, 203

Agency for Toxic Substances and Disease Registry, 46, 54



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Index A Acute lymphocytic leukemia, 48 n.5 Acute myeloid leukemia, 48 n.5, 131 Abbreviated New Drug Application Acute promyelocytic leukemia, 325 (ANDA), 76, 89, 93 Acute respiratory distress syndrome (adult), AbioCor Implantable Replacement Heart, 131 218 n.12, 221 Adalimumab (Humira), 304 n.31, 340, Abiomed, 218 n.12 42 Acceleration of discovery research (see also Adenocarcinoma salivary duct carcinoma, Integrated national strategy) 369 advocacy group approaches, 371-386 Adenoid cystic carcinoma, 369 barriers to, 18 Adenosine deaminase deficiency, 300 n.20 biomarkers as surrogate endpoints and, Advanced Medical Technology Association, 8 237-238 opportunities for, 6-7 Advanced Research Collaboration model, patient registries and, 8 127, 141, 371 task force on, 14, 242, 247-248 Advancing Regulatory Science Initiative, Access to orphan drugs (see also Coverage 102, 103 and reimbursement) Advocacy groups (see also specific groups) advocacy groups and, 83 n.4, 200 activities of, 2, 21, 28, 29, 70, 71 company assistance programs, 83 n.4, consolidation of, 70-71 198-200 educating clinicians, 66 Acetylation, 116, 117, 345, 357 research strategies, 71-72, 137-138, 168, Achondrogenesis type 1A, 127 371-386 Acne rosacea, 318 resource differences, 372-373 Acromegaly, 45 n.3, 328, 330 Aetna, 225 Activa Dystonia Therapy, 221 Agency for Healthcare Research and Acute hyperammonemia, 96 Quality, 10, 133, 193, 203 Acute intermittent porphyria, 368 Agency for Toxic Substances and Disease Acute lymphoblastic leukemia, 298-299, Registry, 46, 54 329, 330, 338, 339 

OCR for page 395
 INDEX Agriculture, Rural Development, Food and cystic fibrosis, 127 Drug Administration, and Related defined, 345, 355 Agencies Appropriations Act of development, 127-128, 380-381 2010, 100 exploratory IND studies, 75, 153 Albright hereditary osteodystrophy, 131 funding for, 132 Alglucosidase alfa (Myozyme), 96, 159, 198 genetically modified animals, 115, 116, Allele, defined, 345, 346 127-128 Alpers syndrome, 368 Huntington disease, 127 Alpha-1 antitrypsin deficiency, 52, 131, 375 infrastructure for, 127-128 Alpha-1 Foundation, 373, 375-377 Marfan syndrome, 113, 162 Alzheimer disease, 15, 141, 147, 167 medical devices, 210 Amanita phalloides (“death cap” naturally occurring diseases, 127 mushroom), 54 preclinical studies, 120, 149, 150, 152, Amatoxin poisoning, 54 153 Ambrisentan (Letairis), 302, 303 n.29, 330, repositories, 6, 7, 143, 347 334 spinal muscular atrophy, 380-381 Amebiasis, 318, 323 Antibiotics, 43, 53, 86 n.6, 293 Amendments to the Patent and Trademark Anthracycline, 55 Act of 1980 (Bayh-Dole Act), 114 Anthrax, 81 American Academy of Pediatrics, 68 Antibodies, 113, 120, 121, 137, 149-150, American Association of Poison Control 151, 152, 300, 339-340, 346, 380, Centers, 46 382 (see also Monoclonal antibodies) American College of Medical Genetics resources, 382 (ACMG), 57-58, 114 Aortic aneurysm, 113, 118, 129, 162 American College of Physicians, 68 Aplastic anemias, 51 American Heart Association, 384 Approval process for orphan drugs and American Institute for Medical and biologics (see also Center for Biological Engineering, 230 Drug Evaluation and Research; American Partnership for Eosinophilic Investigational New Drug) Disorders, 287 accelerated approval, 80, 81, 82, 87, 97, American Recovery and Reinvestment Act, 156, 157 131, 132 access to clinical data supporting/ American Society of Health-System denying approvals, 83-84, 98, 164- Pharmacists, 199 n.10 165, 166-167 American Society of Hematology, 66-67 basics of, 75-77 Aminoglycoside-induced deafness, 368 defined, 346 Aminolevulinate dehydratase deficiency evidence of safety and efficacy accepted porphyria, 368 by FDA, 4, 76-77, 95-98 Amyloidosis, 131 fast track, 80, 81, 87 Amyotrophic lateral sclerosis (ALS), 16, 28, funding, 26 64, 85, 166, 184, 310, 325 generic products, 76, 78, 89, 93 Amyris Biotechnologies, 173 guidance for research sponsors, 4, 13, Andersen-Tawil syndrome, 366 27, 75-76, 98, 99-100 Anencephaly, 56 guidance for reviewers, 6, 27, 98 Angelman, Rett, and Prader-Willi inconsistencies in FDA reviews, 4-5, 13, Syndromes Consortium, 365 95, 99-100, 158-159 Angelman syndrome, 115-116, 365 issues/criticisms of, 4, 95-101 Animal models and studies medical device approval process access to, 6, 7, 128, 139, 143, 380-381 compared to, 216-220 of biologics, 152 neglected tropical disease drugs, 82, 86 carcinogenicity studies, 150 n.7

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 INDEX new indications, 76 funding, 21, 130-134, 168, 291, 374, priority reviews, 80, 81, 82, 86 n.7, 87, 375 300 incentives for, 293 problems with submitted studies, 4, 45, infrastructure for, 7, 9, 19, 66, 113, 114, 98-99 125, 134-135 recommendations, 4-6, 105-107, 159, innovations, 1-2, 6, 20, 109, 111, 112- 244 113, 169, 242, 243 response to problems, 100-101 medical devices, 212 n.7, 231 Special Protocol Assessments, 82, 104 sharing data on, 140 speeding and facilitating, 79-82, 86, 92, training of researchers, 135, 136, 137 101, 155 translation of, 118, 120, 148, 149, 161, trends in designations and approvals, 168, 169, 176, 248, 375 91-92 value of, 6, 40, 62 user fees, 4, 24-25, 26, 30, 79-80, 86, Batten disease, 367 87, 101, 103, 104, 217, 292, 309 Bayesian statistical methods, 163-164, 234 APRT deficiency (dihydroxyadeninuria), Bell Labs, 226 369 Benzene, 51 Arginase deficiency (hyperargininemia), 369 Benzoate-phenylacetate (Ucephan, Argininosuccinate lyase deficiency Ammonul), 299 (argininosuccinic aciduria), 369 Beriberi, 55 Argininosuccinate synthetase deficiency Berns, Scott, 22 (citrullinemia I), 325, 369 Best Pharmaceuticals for Children Act of Arsenic poisoning, 54 2007, 82, 89 Artemether-lumefantrine (Coartem), 86 Bevacizumab (Avastin), 304 n.31 Asbestos, 54, 56 Bile acid synthetic enzyme deficiencies, 119 Aspartylglucosaminuria, 366 Biliary cirrhosis, 326 Atransferrinemia, 16 Bioengineering, 20-21, 230, 231, 346 (see Australia, 30, 32, 33, 302-303 also Medical device R&D) Autism, 49 Bioinformatics, 117-118, 124, 135, 136, Autoimmune autonomic neuropathy, 365 141, 231, 346, 360 Autonomic Rare Diseases Clinical Research Biologics/biological products Consortium, 365 carcinogenicity studies, 150 Autosomal dominant disorders, 35, 55 n.12, coverage and reimbursement, 181, 183, 346 187, 188, 189, 192 n.9, 315, 325, Autosomal recessive disorders, 96, 346 326, 327, 328, 329, 330, 331 definition, 36, 78, 149-150, 346-347 discovery methods, 120-122 B examples, 78 generic, 181, 301 Bacterial corneal ulcers, 325 immune response, 151, 152 Balamuthia mandrillaris, 53 opportunities and obstacles, 121 Balanced Budget Act of 1997, 311 preclinical studies, 149-150, 151, 152 Baroreflex failure, 365 priority review, 82 Basic research (see also Target discovery) protein replacement therapy, 63, 121 access to biological specimens, 159, 243 regulation, 77 n.2, 78, 107, 210, 214 alpha-1 antitrypsin deficiency agenda, n.9 376 trends in approvals, 92-93, 300, 301 centers for, 66 wild-type protein, 152 collaborations and partnerships, 284 Biologics License Application (BLA), 78, defined, 38 164, 167, 237 n.20, 297, 300, 301, epidemiological studies and, 42 346, 347

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 INDEX Biomarkers (see also Genetic factors) Buprenorphine hydrochloride (Subutex, and acceleration of research, 8, 124-125, Buprenex), 92 n.11, 328, 332 157 Buprenorphine with naloxone (Suboxone), data collection and sharing, 174 92 n.11, 328, 332 defined, 347 Bureau of Maternal and Child Health, 132 examples for rare diseases, 116, 158-159 Burroughs Wellcome Fund, 137 FDA initiatives, 102, 105, 168, 171 foundation for discovery, 111, 149 C innovative discovery approaches, 166- 167, 175 Cadmium, 54 knowledge base, 42 California Department of Health Services, NIH Challenge Grants, 158 74, 292-293 proteomic and metabolemic studies, 117, Campbell, Robert, 205 124, 125 Cancer Brain Tumor Registry of the United public-private partnerships, 157-158, States, 17 167, 168 Capsaicin (Qutenza), 302 n.27, 304 n.32 recommendations for effective evaluation Carbamylphosphate synthetase deficiency, of, 158 325, 369 signature molecule, 358 Carcinogenicity studies, 150-151 standards for validation and application, Carglumic acid (Carbaglu), 96, 150 174 Carnitine deficiency, 323 substudy protocol, 175 Causes of rare diseases as surrogate endpoints, 8, 21, 156, 157- fetal exposures, 56-57 158, 166-167, 174, 359, 364 genetic, 1, 16, 20, 22, 41, 51, 52-53 of therapeutic response, 161, 166 infectious agents, 1, 16, 41, 51, 53-54 uses, 157 injuries, 55 validation inadequacies, 4, 8, 99, 174 nutritional deficiencies, 55 Biomarkers Consortium, 157-158, 167, 174 toxic agents, 1, 16, 41, 51, 54 Biorepositories, 6, 8, 22, 45, 125, 129-130, treatment related to another disease, 1, 143, 144, 159, 160, 161, 170, 175, 41, 51, 55 242, 284, 347, 375 Celiac disease, 119 Biotin, 17, 119 Cell (see also Stem cell therapy) Biotinidase deficiency, 119 differentiation, 122, 128, 349 Blepharospasm, 366 research, 128 Blood-brain barrier, 121-122, 347 therapy, 122, 135, 347 Bone marrow or cord blood transplants, 63, Center for Biologics Evaluation and 64, 122 Research (CBER), 4, 77 n.2, 78, 107, Bortezomib, 304 n.31 210, 214 n.9 Bosentan (Tracleer), 302, 303 n.29, 322, Center for Devices and Radiological Health 328, 334 (CDRH), 12-13, 210, 211, 212, Botulinum toxin, 17, 237 n.20 213-214, 216, 220, 222, 234, 238, Botulism, 53, 74, 292-293, 339, 341 239, 240 Botulism immune globulin (BabyBIG), 74, Center for Drug Evaluation and Research 292-293, 339, 341 access to data supporting approvals by, Brain arteriovenous malformation, 365 83-84 Brain Vascular Malformation Consortium, Associate Director for Rare Diseases, 4, 365 91-92 100-101, 105, 106, 149, 246 Breast cancer, 28, 34, 71, 92 n.11, 155, collaboration with OOPD and NIH, 108 214, 228 n.17, 302, 304 n.31, 326, and combination products, 214 327, 330 funding for, 103, 105 Bronchiolitis obliterans, 366

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 INDEX guidelines/guidance for reviewers and Chordoma Foundation, 134 sponsors, 5-6, 77 n.2, 98, 101 n.14, Chorus program, 165 107, 151, 152, 153 Chromium, 54 and historical controls in phase II trials, Chromobacterium violaceum, 53 155 Chronic Graft Versus Host Disease inconsistencies in reviews, 4, 5, 95, 98, Consortium, 366 99, 151, 158, 173 Chronic granulomatous disease, 123, 369 Medical Policy Coordinating Committee, Chronic hepatitis C, 339 101 n.14 Chronic immune (idiopathic) organizational culture, 91, 101 thrombocytopenic purpura, 331 problems with research sponsors, 98, 99 Chronic inflammatory demyelinating recommendations for, 5-6, 105-107, 108 polyneuropathy, 331 resource and personnel challenges, 6, 99, Chronic, intractable (drug-refractory) 103-104, 105 primary dystonia, 221, 237 n.20 roles and responsibilities, 4, 75, 78, 91- Chronic lymphocytic leukemia, 48 n.5, 139 92, 103 Chronic myelogenous/myeloid leukemia Centers for Disease Control and Prevention (CML), 20, 48 n.5, 63, 111-112, (CDC), 17, 36, 46, 54, 58, 67, 102, 118, 298, 305, 327, 330 133, 246, 247, 376 Chronic progressive external Centers for Education and Research on ophthalmoplegia, 368 Therapeutics, 203 Chronic, severe, treatment-resistant Centers for Medicare and Medicaid Services obsessive compulsive disorder, 230 (CMS; see also Medicaid; Medicare), Churg-Strauss syndrome, 309 10, 184 n.3, 185, 186, 188, 189 n.6, CINCH (Clinical Investigation of 190, 192-193, 194, 201, 202, 225, Neurologic Channelopathies), 366 311, 312, 313 Cinacalcet (Sensipar), 322, 328, 334 Central precocious puberty, 338 Citric acid, 316, 318, 324, 332 Cerebrotendinous xanthomatosis (CTX), 83 Citrin deficiency (citrullinemia II), 369 n.4, 369 Clinical and Translational Science Awards, Chagas disease, 31, 142 9, 163 n.2, 170-171, 176 Charcot-Marie-Tooth disease, 366 Clinical Data Interchange Standards Charge to committee, 2-3 Consortium, 156 Chemical compound libraries Clinical endpoints, 166, 347 (see also defined, 349 Surrogate endpoints) high-throughput screening, 119-120, Clinical Laboratory Improvement 139, 171-172, 352-353 Amendments of 1988, 213 sharing, 6, 7, 13, 138, 141-142, 143, Clinical phenotype, 123, 347 144 Clinical research (see also Clinical trials) Chemotherapy, 51 alpha-1 antitrypsin deficiency, 376-377 Chenodeoxycholic acid (Chemix, Bayesian statistical methods, 163-164, Chenodal), 83 n.4, 93 234 Chicken pox, 56 capacity building strategies, 9 Child Health Consortium Oversight consortia, 2, 19, 22, 23, 25, 28, 91, 104, Committee, 170 141, 145, 156, 161-163, 170, 172, Childhood (see also Pediatric) 174, 222, 223, 365-369 (see also cancers, 34, 162, 338 specific organizations) Children’s Oncology Group (COG), 9, 161, defined, 39-40 162, 176 effectiveness, 40 Children’s Tumor Foundation, 67, 287 efficacy, 40 Chloramphenicol, 51 grants, 37 Cholesterol processing disorders, 15 historical case series, 4

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00 INDEX medical devices, 37, 231-234 placebo concurrent control, 5, 77, 96, toxicology studies, 4, 95, 99, 107, 152 97, 98, 155, 298, 305, 307, 348, 357 training, 133, 134-137, 164 population size constraints, 20, 95, 96- types, 39 98, 100, 112, 142, 154, 155, 159 Clinical Research Consortium for recommendations (3-2), 5-6, 107-108, Spinocerebellar Ataxias, 366 242, 243, 244 Clinical trials registries, clearinghouses, and databases, active treatment concurrent control, 77, 45 n.3, 84, 166, 167 345 sharing information on results, 83-84, adaptive design strategies, 77, 98, 162, 164-165, 166-167, 177 164, 234, 345 single-arm, 96, 159, 305 biomarker substudy protocol, 175 Special Protocol Assessments, 82, 104 characteristics of adequate and well- surrogate endpoints, 4, 8, 21, 81, 95, controlled studies, 76-77 99, 107, 109, 156, 157-159, 160, communicating with FDA about, 4, 75- 166-167, 174, 175, 233, 240, 242, 76, 99, 104, 107, 152 243, 244, 298, 305, 307-308, 359, costs, 161 364 defined, 39, 348 training and career development for dose-comparison concurrent control, 77, researchers, 133, 134-137, 144-145, 350 156, 164 education/guidance for sponsors and Clofazimine (Lamprene), 317, 318, 323, reviewers, 5, 30, 75-76, 77, 100, 332 101, 107, 108 Clostridium botulinum, 74, 339 funding, 102, 103, 107, 132 Coalition Against Major Diseases, 167, 168 generic drugs, 75, 89 Cochrane Collaboration, 61 n.16 good clinical practice principles and Colchicine (Colcrys), 77, 96-97, 172, 180- guidelines, 154 181, 302 n.27, 305 n.33 historical controls, 77, 154, 155, 244, Collagenase clostridium histolyticum 305, 353 (Xiaflex), 37, 97 innovative designs and data analysis Columbia University Medical Center Spinal strategies, 5, 163-164, 175 Muscular Atrophy Clinical Research insurance coverage, 183, 185, 200-201 Center, 382 international harmonization of, 29 Combination products, 74, 94, 102, 214- negative FDA findings, 83-84, 164-165, 215, 219-220, 236, 299, 348 166-167, 177 Combined immunodeficiency, 35, 121, 123, no treatment concurrent control, 77, 356 300 n.20, 369 noninferiority, 77, 356 Commission for the Control of number required by FDA, 76, 95, 155 Huntington’s Disease and Its patient registries and, 159, 161 Consequences, 23, 24 pediatric studies, 82, 89 Committee of the Public Health Service, 24 phase I (safety), 39, 81, 82, 94, 96, 99, Committee to Combat Huntington’s 148, 150, 152-154, 297, 298, 305, Disease, 29 307, 308, 348, 384 Commotio cordis, 55 phase II (proof of concept/efficacy), 4, Condition, defined, 32 39, 81, 82, 94, 96, 148, 152, 154, Confetti-like macular atrophy, 35 155, 298, 305, 307, 348 Congenital diaphragmatic hernia, 131 phase III (regulatory proof), 4, 39, 76, Congenital disorders of glycosylation, 117 81, 94, 95, 96, 97, 99, 108, 118, Congenital heart disease, 222 148, 152, 154-155, 167, 298, 305- Congenital hypothyroidism, 58, 119 306, 348, 384 Congenital porphyria, 368 phase IV (see Postmarketing studies Congressionally Directed Medical Research requirements) Programs, 28, 133

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0 INDEX CoQ deficiency, 368 Cystic fibrosis transmembrane conductance Coronary artery disease, 113 regulator, 138 Coverage and reimbursement (see also Cystic hydatid disease, 326 Medicaid; Medicare) Cystine nephrolithiasis, 323 Affordable Care Act and, 79 Cystinosis, 64, 325, 366 biologics, 181, 183, 187, 188, 189, 192 Cystinosis Foundation, 26 n.1 n.9, 315, 325, 326, 327, 328, 329, Cystinuria, 323, 326, 369 330, 331 clinical trials, 183, 185, 200-201 D drugs, 10, 184-198, 323-331, 341-342 generic products, 189, 190, 194, 196, Dalkon Shield, 209 197, 312, 314, 321 Dana Foundation, 137 Genetic Nondiscrimination Act, 25 Danon disease, 366 genetic tests, 60, 183-184 Data exclusivity rules, 88-89, 349 medical devices, 183, 186, 200, 201, Data sharing (see Sharing data and 224-225, 310 resources) off-label use, 10, 26, 191-193, 198, Databases and data resources 202-203 approved drugs, 139 pricing of drugs and devices, 9-10, 179, clinical trial review findings, 83-84, 180-181, 183, 187, 189, 190, 191, 164-165 193-194, 196, 197, 198, 199, 201 generic orphan drugs, 295, 315 private health plans, 182, 197-198 OMIM, 34, 35 n.7 recommendations, 10, 201-202, 245 orphan drugs, 91 transition from pediatric to adult care Orphanet, 33-34, 35, 36, 46, 48, 93 and, 68 n.12 Critical Path Initiative, 8, 95, 102, 109, product research grants lists, 94 168, 171, 174, 242 DeBakey VAD Child Left Ventricular Assist Critical Path Institute (C-Path), 168, 169 System, 207, 221 Critical Path to TB Drug Regimens, 169 Deep brain stimulation devices, 17, 229, Crohn’s disease, 327 230, 235, 237 Cromolyn sodium (Opticrom), 323 Deferasirox (Exjade), 55 Crotalidae polyvalent immune fab (ovine) Delivery of health care services (CroFab), 54 comprehensive care centers, 66-67 Cryopyrin-assisted periodic syndromes, 331 medical home, 68-69 Cryptosporidiosis, 131, 327 pediatric-adult care transition, 67-69 Cures Acceleration Network, 9, 170, 172- physician contacts, 67 173, 176, 177, 242 Demonstration projects Custom devices, 222-224, 349 Dengue fever, 38 Cutaneous sclerosis, 366 Dent’s disease, 369 Cutaneous T-cell lymphoma, 327, 330 Department of Defense, 28, 133, 184, 246, Cyanide poisoning, 54, 63 247 Cysteamine (Cystagon), 64, 325, 334 Department of Health and Human Services, Cystic fibrosis, 19-20, 42, 51, 57, 59, 61 22, 57, 84 n.5, 166, 198 (see also n.16, 65, 122, 125, 127, 131, 135, specific agencies) 158, 187, 277, 366, 378 Medicaid Rebate Program, 196 Cystic Fibrosis Foundation (CFF), 29, 61, National Commission on Orphan 66, 129, 133, 134, 137-138, 372, Diseases, 26 373, 377, 378 Office of the Inspector General, 91, 199 Cystic Fibrosis Foundation Therapeutics, n.11 Inc., 162, 378-379 recommendations for, 14, 174, 247

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0 INDEX Department of Veterans Affairs, 311 n.3 Dopamine beta hydroxylase deficiency, 365 Dermatofibrosarcoma, 299 Dornase alfa (Pulmozyme), 187 Dexrazoxane (Totect), 55 Doxorubicin liposome (Doxil), 304 n.31, Diabetes and deafness (DAD), 368 327, 332 Diagnosis of rare diseases (see also Drug delivery innovations, 232 Biomarkers) Drug Price Competition and Patent Term accuracy and timeliness, 20, 59 Restoration Act of 1984 (Hatch- companion diagnostic test, 74, 105, 214, Waxman Act), 88 219, 348-349 Drug-resistant strains of infectious diseases, genetic tests, 57, 58, 60, 124, 125, 183- 38, 42, 53 184, 213, 228 n.17, 283, 351, 382 Drugs (see also Orphan drugs) imaging services and technologies, 102, defined, 36, 350 123, 124, 137, 186, 206, 212, 231 off-label use, 37 implanted laboratory-on-a-chip, 232 Drugs for Neglected Diseases, 141 insurance coverage, 60 Druker, Brian, 111, 112 newborn screening, 17, 46, 57-59, 64, Duchenne muscular dystrophy, 52, 59, 63, 117, 124, 125, 377 113, 131 obstacles to, 59-60 Dupuytren contracture, 37, 97 orphan drugs for, 37 Dystonia Coalition, 366 phenotyping, 123, 125, 127, 136, 164, Dystonia Medical Research Foundation, 357 26 n.1 regulation of devices for, 124, 212-214 Dystonias, 17, 221, 366 SMN (human) ELISA Kit, 380 standardization of approaches, 60-61 E technologies, 123-125 Undiagnosed Diseases Program, 59, 67 Economic costs of rare diseases, 69-70 Diamond-Blackfan anemia, 64 Effectiveness, defined, 40, 350 Dietary avoidance therapy, 119 Efficacy, defined, 40, 350 Dietary supplements, 54 n.10, 56, 63 Eflornithine (Vaniqa), 172 n.3 Dihydropyrimidine dehydrogenase gene Ehlers-Danlos syndrome, 130, 131 mutation, 55 n.12 Electronic health records, 46, 66 Discovery research (see also Acceleration Eli Lilly and Company, 141, 142, 165-166, of discovery research; Infrastructure 299 for research; Target discovery; Emphysema, 235 Therapeutics discovery) Encephalomyopathy, 368 basic research and, 19-20, 111 Encephalopathy, 133, 368 challenges and opportunities, 1, 19-22 End-of-life care, 65 historical and policy context, 22-30 End-stage heart disease, 218 n.12, 221 innovative platforms, 137-142 End-stage renal disease, 184, 310, 324 organized research on exceptionally rare Endpoint (see also Clinical endpoints; diseases, 22 Surrogate endpoints) recommendations, 142-146 defined, 350 time line of policy-related events, 24-25 Enlight Biosciences, 140-141 Disease, defined, 32 Environmental modification/adaptation, 63 Disorder, defined, 32 Environmental Protection Agency, 156 DNA Enzo Life Sciences Inc., 380 analysis tools, 112 Enzyme replacement therapy, 62, 63, 64, methylation, 115-116, 349, 355 78, 88, 96, 121-122, 150, 300, 328 modification, 115-116, 124, 349 Eosinophilia-myalgia syndrome, 54 repositories, 22, 127, 347, 375 Eosinophilic leukemia, 298 sequencing, 116, 125, 127, 349-350 Epicel (cultured epidermal autografts), 221

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0 INDEX Epidemiology of rare diseases (see also Familial dilated cardiomyopathy, 131 Prevalence of rare diseases) Familial dysautonomia, 57 condition-specific codes, 46 Familial hypercholesterolemia, 113 factors affecting data, 42 Familial Mediterranean fever, 35 n.7, 96-97, genotype-phenotype correlations, 45, 36 180 n.4 Fanconi anemia, 15, 51, 52, 122, 131, 132 incidence rates, 17, 43, 44, 45-46, 47- Fanconi Anemia Research Fund, 133, 286 48, 49, 57, 128, 215-216, 353, 358 Farber’s syndrome, 46, 367 national data collection programs, 45-46 FasterCures, 372 natural history studies, 4, 6, 22, 42, 44- Federal Food, Drug, and Cosmetic Act, 75, 45, 71, 98, 99, 128, 132, 135, 145, 77, 78, 96, 180, 209, 302 n.27, 347, 159, 244, 353, 376-377 354 newborn screening programs, 46 Fee waivers, 4, 24-25, 26, 30, 79-80, 86, objectives of epidemiologic research, 42, 87, 217, 292, 309 44 Felbamate (Felbatol), 303, 338, 342 policy uses of data, 44 Fibrodysplasia ossificans progressiva (FOP), prevalence data, 1, 17, 47-51 47, 67, 287 single-disease studies, 45 First Data Bank, 315, 318 sources of data, 45-46 Fludarabine phosphate (oral), 90 Epigenetics, 15, 44, 115-116, 118, 124, 5-Fluorouracil, 55 n.12 125, 155, 350 Focal and segmental glomerulosclerosis, 367 Episodic ataxias, 366 Folic acid supplementation, 56 Erythema nodosum leprosum, 56, 318, 323, Food and Drug Administration, 2, 376 (see 327 also Approval process for orphan Erythropoietic protoporphyria, 368 drugs and biologics; Center for Ethical issues, 44, 55, 57, 77 n.2, 125, 234- Biologics Evaluation and Research; 235, 377 Center for Drug Evaluation and European Medicines Agency, 29, 48 n.8, 168 Research; Regulation of orphan European Rare Diseases Therapeutic drugs and biologics) Initiative, 142 Advancing Regulatory Science Initiative, European Union 102, 103 coding of rare diseases, 46 agency-wide concerns, 101-103 definition of rare disease, 32, 33, 34, 47 complexity of work of, 73 EPPOSI workshop on patient registries, Critical Path Initiative, 8, 95, 102, 109, 160 168, 171, 174, 242 Orphanet, 33-34, 35, 36, 46, 48, 93 n.12 grants program for orphan products, 4, policy incentives for orphan drug 133 development, 29, 30 guidance on animal carcinogenicity prevalence of rare diseases, 33-34, 48, studies, 150, 151 93 n.12 interagency collaborations, 156 survey of rare diseases, 59 international initiatives, 29 Treat-NMD Clinical Research Initiatives, Medical Device Reporting system, 219 382 Neurologic Drugs Advisory Committee, Exome sequencing, 116, 124, 125, 349-350 23 NIH-FDA Leadership Council, 106 Office of Combination Products, 214 F Office of Orphan Products Development, 28, 30, 87, 88, 90-91, 92, 100, 101, Fabry disease, 46, 121, 366 104-105, 108, 109, 172, 206, 210, Familial bilateral striatal necrosis (FBSN), 368 215, 220, 222, 292-293, 295, 372 Familial breast cancer, 33 referral of grant applications to NIH, 109 Familial cavernous malformations, 365

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0 INDEX G repurposing existing drugs, 171-172 resources and organization, 4, 27, 79- Galactosemia, 64 80, 101-105 Galactosialidosis, 367 statutory authority, 75 Galsulfase (Naglazyme), 150, 187 “transparency” initiative, 84, 166-167 Gangliosidosis, 367 Food and Drug Administration Gastric cancer, 131 Amendments Act, 25, 84, 109, 166 Gastrointestinal stromal tumor, 61, 298 Food and Drug Administration Gates Foundation, 173 Modernization Act of 1997, 76, 84, Gaucher disease, 46, 63, 64, 121, 180, 328, 87, 89, 156, 166 367 Forced expiratory volume, 158-159 Gemtuzumab ozogamicin for injection Foundation for the National Institutes of (Mylotarg), 81 Health, 157-158, 167, 174 GenBank, 127 Fragile X syndrome, 57, 287 Gene, defined, 350 Freedom of Information Act, 83 n.4, 302 Gene expression n.23, 304 n.31 analysis/profiling, 116, 117, 124, 125, Friedreich’s ataxia, 52, 169, 382-383 351 Friedreich’s Ataxia Research Alliance, 128, defined, 350-351 373, 382-384 Gene mapping, 114-115, 351 Frontotemporal dementia, 373 Gene products, 62, 114, 351 Fucosidosis, 367 Gene therapy/transfer, 62, 63, 122-123, Fujirebio Mesomark Assay, 212 n.6 135, 351, 377, 379 Funding Gene transcription, 116, 349, 350-351, 355, advocacy groups and foundations, 28, 360 29, 132, 133-134, 141, 172-173 GeneClinics, 382 animal model development, 127-128 Genentech, 299 basic research, 21, 130-134, 168, 291, Generic orphan products 374, 375 approval process, 76, 78, 89, 93 for biomedical research, by source, 28 availability, 93, 181, 296, 301, 315, clinical research consortia, 161-162 321, 323-327, 329 clinical trials, 102, 103, 107, 132 biologics, 181, 301 commercial sources, 28, 29 challenges to innovator patents, 89 n.9 epidemiological data and, 44 clinical trials, 75, 89 FDA grants under HDE, 4, 26, 29, 30, competitiveness, 10, 181, 301, 303 n.28 37, 74, 86, 87, 91, 94 databases, 295, 315 foreign governments, 134 exclusivity rules and, 88-89, 90, 181, inadequacies, 156 301 information sharing tied to, 127, 141 incentives for development, 88-89 landscape analysis, 374 insurance coverage, 189, 190, 194, 196, NIH and other federal agencies, 21, 27, 197, 312, 314, 321 28, 102, 103, 127, 130-133, 134, market share for orphan drugs, 93 161-162, 172-173 new orphan drug approval for orphan products grants program, 6, 12, discontinued drugs, 93 94, 108-109 pricing, 181, 190, 196, 197 preclinical research, 132 public availability of FDA review, 83 prevalence of disease and, 130-132 GeneTests, 60, 382 tracking and coordinating, 27 Genetic Alliance, 42, 70, 284, 372 training of researchers, 135, 136, 137, Genetic Alliance Biobank, 129 144-145 Genetic and Rare Diseases Information young investigator awards, 137 Center, 33 Fusobacterium necrophorum, 53

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0 INDEX H Genetic Disorders of Mucociliary Clearance, 366 H1N1 virus, 228 n.17 Genetic factors Hamburg, Margaret, 73 autosomal dominant disorders, 35, 55 Heartsbreath test, 212 n.6 n.12, 346 Hemochromatosis, 32, 36, 63 autosomal recessive disorders, 96, 346 Hemophilia, 67, 121, 122, 127, 324 causes of disease, 52-53 Hepatitis, 51 chance mutations, 53-54 Hepatocellular carcinoma, 97, 304 n.31 microarray methods, 116 Hepatocerebral disease, 368 multiple-gene, 53, 115 Hepatoerythropoietic porphyria, 368 mutations, 16, 22, 36, 51, 52-53, 55 Herbal supplements, 54 n.12, 60, 113, 115, 118, 123, 124, Hereditary 130-131, 214, 355, 356, 365, 373- coproporphyria, 368 374, 381 hemorrhagic telangiectasia, 45 n.3, 365 pharmacogenetics, 124 inclusion body myopathy, 139 scientific and technical advances, 54 spherocytosis, 65, 131 screening and counseling programs, 57, tyrosinemia type 1, 128, 328 58, 65 Herpes virus, 51 single-gene defects, 22, 52 Histones, 115-116, 125, 353 susceptibility to infectious diseases, 53- Histrelin acetate (Supprelin LA), 90, 338, 341 54, 116 HIV/AIDS, 42, 81, 169, 189, 228, 300, traditional genetic studies, 20, 114-117 312, 323, 324, 326, 327, 338 variants of diseases, 52 Holocarboxylase synthetase deficiency, 17 Genetic Information Nondiscrimation Act Homeopathic Pharmacopoeia of the United of 2008, 25, 70, 71 States, 350 Genetic tests/testing, 57, 58, 60, 124, 125, Homocystinuria, 326 183-184, 213, 228 n.17, 283, 351, Hookworm, 139 382 Human genome sequencing, 112 Genome Human growth hormone, 93, 298, 299, defined, 351 318, 329 (see also Somatropin) sequencing, 112, 116, 124, 125 Humanitarian Device Exemption (HDE) Genome-wide association studies, 115, 352 administration, 91, 210 Genomics Portal, 141 approvals, 218, 220, 222, 237 Genotype, 36, 45, 46 n.4, 58, 128, 248, clinical studies, 11, 212, 217, 223 n.13, 352, 357 236 Genotyping, 124, 127, 352 combination products, 214, 236, 237 n.20 Genzyme, 45 n.3 comparable devices, 216, 217 Giant cell (temporal) arteritis, 369 coverage and reimbursement, 66, 218, Giardiasis, 302-303, 318, 328 224-225 Glatiramer acetate (Copaxone), 322, 326, defined, 253 334 diagnostic devices, 215 GlaxoSmithKline, 142 eligibility, 11, 215-216, 238 Glioblastoma multiformae, 17, 304 n.31 examples of approved devices, 211, 212, Global Forum for Health Research, 138 n.2 221, 230, 235, 237 Glucono-delta-lactone, 316, 318, 324, 332 guidance and assistance for device Glutamine (Nutrestore), 317, 318, 329, 332 sponsors, 13, 219, 238, 240, 244, Gordon, Leslie, 22 245 Gorham’s disease, 52 incentives offered by, 11, 12, 27, 86, Government Accountability Office (GAO), 208-209, 216-220, 238-239 81, 157, 180, 190-191, 222, 238, 308 and innovation, 234-237, 283 Graft versus host disease, 122, 366

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0 INDEX N Metachromatic leukodystrophy, 45 n.3, 46, 367 N-Acetylglutamate synthase deficiency, 96, Metronidazole topical (Metrogel), 317, 318, 369 323, 332 Naegleria fowleri, 53 Mevalonic aciduria, 369 Nanotechnology, 102, 124, 231, 232 Microarray methods, 116, 230, 351, 355 Narcolepsy (cataplexy), 131, 327, 328 Microfluidic devices, 124 National Cancer Institute MicroRNAs (miRNAs), 116, 355 animal models, 128 Microscopic polyangiitis, 369 Children’s Oncology Group, 9, 161, Midodrine (ProAmantine), 308, 326, 334 162, 176 Milk thistle extract, 54 definition of rare cancers, 48 n.6 Miniaturization, 226, 232 SEER program, 46, 47, 48 n.5 Minimal change disease, 367 National Center for Biotechnology Mitochondrial Information, 60, 126-127 Complexes I–V deficiencies, 368 National Center for Research Resources, DNA depletion syndrome, 368 170 encephalopathy lactic acidosis, 368 National Chemical Genome Center, neurogastrointestinal 171-172 encephalomyopathy, 368 National Commission on Orphan Diseases, Modafinil (Provigil), 319, 327, 334 24, 26, 59 Modifier gene, 52, 115-116, 125, 355, 376 National Disease Research Interchange, 129 Monoclonal antibodies, 78, 118, 213, 300, National Drug Code, 314 n.10, 315 355 National Formulary, 209, 350, 354 Morquio syndrome, 367 National Foundation for Infantile Paralysis, Mouse models (see Animal models and 134 studies) National Health Council, 376 Mucoepidermoid carcinoma, 369 National Heart, Lung, and Blood Institute, Mucolipidosis, 367 45, 66, 134, 162, 230-231 Mucopolysaccharidosis, 45 n.3, 121, 330, National Human Genome Research 367 Institute, 33 Multiple myeloma, 56, 141, 180, 200, 304 National Huntington’s Disease Association, n.31 26 n.1 Multiple Myeloma Research Consortium, National Institute of Biomedical Imaging 141, 162 and Bioengineering, 231 Multiple Myeloma Research Foundation, National Institute of Neurological Disorders 372 and Stroke (NINDS), 139, 382 Multiple respiratory chain enzyme National Institutes of Health (see also Office deficiencies, 368 of Rare Diseases Research; individual Multiple sclerosis, 55, 324, 325, 326, 371 centers and institutes), 376 Multiple sulfatase deficiency, 367 action plan for rare diseases Multiple system atrophy, 365 (recommended), 7, 144, 145-146, Muscular dystrophy, 28, 52, 59, 63, 85, 164, 242, 243, 245-245 113, 131, 135, 226 Biomarkers Consortium, 157-158, 167, Muscular Dystrophy Association (MDA), 174 168, 372, 384 career development awards, 137 Mycobacterium avium complex disease, 324 Center for Scientific Review, 145 Myelin Repair Foundation, 127, 141, 371 Challenge Grants, 158 Myelodysplastic syndromes, 329 Chemical Genomics Center, 139 Myeloproliferative disease, 298-299 Child Health Consortium Oversight Myoclonus, 85, 368 Committee, 170

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 INDEX Clinical and Translational Science National Registry of Genetically Triggered Awards, 9, 136, 163 n.2, 170-171, Thoracic Aortic Aneurysms 176 and Cardiovascular Conditions data/resource sharing initiatives, 6-7, (GenTAC), 129 127, 129, 142-144, 173-174 National Toxicology Program, 150 design of product development studies, Natural history studies, 4, 6, 22, 42, 44-45, 6, 108-109, 243, 245 71, 98, 99, 128, 132, 135, 145, 159, Director’s Pioneer Awards, 145 164, 244, 353, 376-377 FDA-NIH coordination/cooperation, Neglected diseases (see also specific diseases) 5-6, 9, 12, 27, 74, 98, 108, 145, 156, defined, 37-38, 356 223 FDA review group, 100 FDA referral of grant applications to, innovation platforms, 165, 168-169, 243 109 international efforts, 53, 172 n.3, 243 funding for rare diseases research, 27, NIH program, 139 45 n.3, 130-133, 134, 136, 137, 149, priority review vouchers for, 82 203, 374 public-private partnerships, 138, 139, GenBank, 127 142, 149, 168-169 and integrated national strategy, 242, sharing resources, 141-142, 173 247 training of investigators, 136 interagency collaborations, 156 TRND program, 2, 29, 139, 171, 174 natural history studies, 45 n.3 tropical diseases, 3, 31, 37-38, 82, 138, Newborn Screening Translational 149 Research Network, 58 NeoGram Amino Acids and Acylcarnitine NIH-FDA Leadership Council, 106 Tandem Mass Spectrometry Kit, 210 Pathway to Independence awards, 144 n.4 preclinical development service, 7-8, Nephropathic cystinosis, 64, 325 173-174, 243, 245 Nephrotic Syndrome Rare Disease Clinical RAID program, 139, 169-170, 171, 174 Research Network (NEPTUNE), 367 Rare Diseases Clinical Research Netherlands, 138 n.2 Network, 2, 8, 9, 19, 21, 25, 28, 45, Neural tube defects, 56 52, 67, 71, 135, 145, 162, 163, 171, Neurofibromatosis, 26 n.1, 28, 44, 45, 131 175-176, 365-369 Neurofibromatosis Clinic Network, 67 recommendations for, 6-8, 108-109, Neuronal ceroid lipofuscinosis, 63 129, 142-144, 145-146, 164, 173- Neuropathy, ataxia and retinitis pigmentosa 174, 242, 243, 245 syndrome, 368 RePORTER database, 130 New Drug Application (NDA), 81, 86, resource allocations, 20-21 89, 91, 93, 99, 104, 148, 155, 164, review mechanisms for rare diseases 166-167, 180, 217, 294, 297, 300, research proposals, 135, 145, 163 301-302, 304, 346, 356 (see also Roadmap, 139, 169 Approval process for orphan drugs Small Business Innovation Research and biologics) program, 173 abbreviated, 76, 89, 93 National Marfan Association, 26 n.1, 134 supplemental, 76, 302 n.23, 307 National Neurofibromatosis Foundation, New molecular entities (NMEs), 82, 89, 90, 26 n.1 92-93, 97-98, 136, 140, 292, 294, National Organization for Rare Disorders 295, 300, 302, 315 (NORD), 24, 26, 34, 42, 61, 70, 71, New York Heart Association, 303 n.29 199-200, 206, 284, 310, 313, 318, Newborn screening, 17, 46, 57-59, 64, 117, 372 124, 125, 377 National Rare Disease Biospecimen Newborn Screening Translation Research Resource, 129 Initiative, 58

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 INDEX Newborn Screening Translational Research amendments, 24, 26 Network, 58 definition of rare disease, 2, 16, 23, 24, Niemann-Pick disease, 46, 61, 131, 132, 25, 32 139, 367, 369 enactment, 23, 24 Nilotinib (Tasigna), 305, 330, 334 indication definition, 309 n.1 Nocardiosis, 17 FDA authority, 2, 292 Nondystrophic myotonic disorders, 366 pupose of, 126 Non-Hodgkin lymphoma, 131 Orphan drug R&D (see also Clinical trials; Noonan syndrome, 131, 304 n.31, 330 Infrastructure for research, drug North American Mitochondrial Diseases development; Regulatory policy Consortium, 368 incentives; specific products) Northern epilepsy, 367 advocacy group models, 168 Novo Nordisk, 299 biologics, 149-150, 151, 152 Nucleotide, defined, 356 chemistry, manufacturing, and controls Nutritional therapies, 63 information, 151 costs, 73-74, 147, 151 current good manufacturing practice, O 151 defined, 40 Octreotide acetate (Sandostatin LAR), 90 FDA programs, 8, 95, 102, 109, 168, Off-label use, 10, 26, 37, 191-193, 198, 171-172, 174, 242 202-203, 216, 229, 245, 360 (see foreign and international initiatives, also Indications for drugs or devices) 29-30 Office of Rare Diseases Research, 30, 45 funding, 23, 172-173 creation of, 24, 25, 27-28, 71 good laboratory practice, 151 funding and resources, 130, 246 grants, 6, 94 list of rare diseases, 33, 36, 54, 55, 56 industry models, 165-168 mission, 246 innovative platforms for, 165-173 partnerships with advocacy groups and medical device R&D compared to, foundations, 134, 372 207-209 Rare Diseases Clinical Research NIH programs, 149, 169-171 Network, 2, 8, 9, 19, 21, 25, 28, 45, outsourcing, 165-166 52, 67, 71, 135, 145, 162, 163, 171, preclinical research, 7-8, 81, 149-152 175-176, 365-369 precompetitive models, 140-141, 144, recommendations for, 9, 176 166-167 and registries and repositories, 160 process, 147-148 TRND program, 2, 29, 139, 171, 174 public-private partnerships, 167, Ohio State University, 381 168-169 Onchocerciasis (river blindness), 31, 172 n.3 recommendations, 7-9, 173-177 Online Mendelian Inheritance in Man by state agencies, 74 (OMIM) database, 34, 35 n.7 Orphan drugs (see also Approval process OP-1 Putty, 214 for orphan drug and biologics; Organ transplants, 62, 63, 64, 187, 198, Infrastructure for research, drug 200, 232, 312, 329, 377 development; Orphan drug R&D; Ornithine transcarbamylase deficiency, 325, specific drugs) 369 approvals by FDA, 2, 21, 92-93, Ornithine translocase deficiency syndrome, 147-148 369 compendium of off-label uses, 10 Orphan Drug Act (see also Humanitarian database, 91 Device Exemption; Innovation effects defined, 37 of Orphan Drug Act; Regulatory mechanism of action unclear, 64-65 policy incentives) medical devices compared to, 206-207 advocacy groups and, 71

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 INDEX Medicare-relevant drugs by exclusivity defined, 159 date and indication, 323-331 epidemiological studies, 45, 128, 159 small-molecule compounds, 62, 63, 90 fee-based curation, 160 n.10, 120, 149, 151, 156, 181, 208, funding for, 246 228, 300, 377 genetic information combined with, 128 types of drugs approved, 93 infrastructure capacity building, 125, Orphan medical products (see also Medical 129, 149, 156, 160, 284, 375, 382 devices for small populations) mandatory participation in, 161 defined, 37 model for, 129 development challenges, 16 natural history studies, 159, 244 Orphanet, 33-34, 35, 36, 46, 48, 93 n.12 organization of, 128-129 Osteogenesis impefecta, 123 phenotypically related diagnoses, Osteoporosis, 302, 304 n.31 128-129 Osteoporosis-pseudoglioma syndrome, 113 postmarketing studies, 83, 96, 159, 298, Ovarian cancer, 16, 28, 44, 324, 327 306 privacy protection, 160 public-private partnership, 160, 242 P recommendations, 8, 129, 175, 242, 244 standardization, 8, 129-130, 143, 144, Paget Disease Foundation, 26 n.1 160-161, 175 Pancreatic cancer, 47-48, 200 as surrogate endpoints, 159-160, 244 Pancreatic Cancer Action Network, 287 toxic substance exposures, 46 Parenchymal neurocysticercosis, 326 uses, 128-130, 159-161, 244 Parkinson disease, 167, 230, 324, 328 workshops on, 160 Parkinson’s Disease Foundation, 26 n.1 Pearson syndrome, 368 Paroxysmal nocturnal hemoglobinuria, 64, Pediatric (see also Childhood; Infantile) 200 -adult care transition, 67-69 Patent ductus arteriosus, 340 cancers, 15 Patent foramen ovale, 220 n.13 clinical trials, 82 Patents, 23, 60 devices, 11, 12, 25, 220-222, 237, 238, cost considerations, 126 244 and data sharing, 126 drugs, 89, 338-342 and generic drugs, 88-89, 90, 181 research consortia, 9, 161, 162, 176 on genes and proteins, 126 Pediatric Heart Network, 134, 162 licensing, 209, 381 Pediatric Medical Device Safety and market exclusivity and, 74, 87, 88-90, Improvement Act, 25, 222 208, 209, 294 Pediatric Research Equity Act of 2003, 82 maximum effective, 294 Pegademase bovine (Adagen), 300 n.20 medical devices, 208, 209, 216 Pentosan polysulfate sodium (Elmiron), 150, term restoration, 88, 209 326, 332 Patient Advocate Foundation Co-Pay Relief Personalized medicine, 20, 202, 248, 351, Program, 200 356 Patient Protection and Affordable Care Act Pfizer Inc., 142, 170 of 2010, 70, 78, 170, 181, 182, 183, Pharmaceutical Assets Portal, 170 189, 195-196, 197, 198, 201, 202, Pharmaceutical Manufacturers Association, 229 n.18, 312 n.4 23 Patient registries (see also specific registries) Pharmaceutical Research and Manufacturers biorepository links, 159-160 of America, 23, 77 n.2, 167 Cancer Brain Tumor Registry, 17 Pharmacia, 299 and clinical trials, 159, 161 Pharmacogenomics, 55 n.12, 124, 184 n.3 data sharing, 8, 160, 175 Phenomics, 124

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 INDEX Phenotype-genotype correlations, 36, 45, 46 Premarket approval application, 11, 211, n.4, 128 215, 216, 217-218, 220 n.13, 222, Phenotypes/phenotypic variation, 36, 44, 223, 230, 231, 233, 234, 235, 236, 51, 113, 115, 129, 143, 357, 359, 239, 240, 346, 349, 353, 358 381 Prescription Drug User Fee Act of 1992, 79 Phenotypic Drug Discovery Initiative, 142 Prevalence of rare diseases Phenotyping, 123, 127, 136, 164, 357 and approvals of orphan drugs, 4-5, 93, Phenylalanine, 63, 158 98, 106 Phenylketonuria, 20, 63, 68, 158, 331 and biomarker validation, 157 Phosphate, 63 complete prevalence, 47 Phosphine, 54 data sources, 33-34, 45-46, 48-49, 128, Pilot projects, 10, 133, 137, 139, 162, 165, 129, 130 189, 203, 229 n.19, 233 defined, 43, 353, 358 Placebo, defined, 357 distribution of rare conditions, 1, 48, 49, Pneumocystis carinii pneumonia, 324 93 n.12 Poisonings, rare, treatment of, 54 documentation to support “orphan” Polyarteritis nodosa, 369 designation, 44, 87, 90-91, 100 Polymorphisms, 116, 124, 125, 352, 357, estimates for specific diseases, 17, 47, 48 358-359 n.7, 180 Pompe disease, 96, 121, 159, 198, 329, 367 marketing exclusivity and changes in, 43 Porphyria Consortium, 368 n.1, 216 Porphyria cutanea tarda, 368 measurement and expression of, 44, Postmarketing studies/requirements, 148 47-48 carcinogenicity studies, 150 reliability of data, 43, 48, 50 defined, 39, 348, 357 and research constraints, 112 difficulty completing, 97-98 and resource allocation, 44, 57, 130, examples of approvals with, 96, 97, 212 131, 132 medical devices, 210, 212 thresholds for “rare” definition, 32-33, monitoring and reporting requirements, 34, 47, 85-86, 215-216 156, 157 Prevention of rare diseases pediatric studies, 82, 96 cost-effectiveness, 58 purpose of and rationale for, 39, 40, 62 epidemiological significance, 42 registries for, 83, 96, 159, 167, 298, 306 newborn screening programs, 17, 46, REMS, 79 n.3, 82-83, 298, 306 57-59, 64, 117, 124, 125 scope of this study regarding, 31, 39 orphan drugs, 37 surrogate endpoints in phase III trials primary, 55-57 and, 81 progressing, 20 trends in requirements for, 298, 305, secondary, 57-59 307, 308 tertiary (see Treatment of rare diseases) withdrawal of approval based on, 156 Prices/pricing of orphan products, 181, 190, Prader-Willi syndrome, 46 n.4, 48 n.7, 115- 196, 197 116, 339, 365 Primary ciliary dyskinesia, 65, 131, 132, Preclinical research, 7-8, 40, 81, 89, 95, 366 100, 107, 108, 120, 128, 132, 139, Primary hyperoxaluria, 63, 369 145, 146, 147, 148, 149-152, 153, Primary Immune Deficiency Treatment 162, 168, 169, 172, 173, 174, 211- Consortium, 368-369 212, 227, 242, 243, 357-358 (see Product development, defined, 40 also Animal models and studies; Progeria, 21, 22, 131, 132 Basic research) Progeria Research Foundation, 22, 53, 371 Predictive Safety Testing Consortium, 168 Progressive multifocal leukoencephalopathy, 55

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 INDEX Proteins Rare diseases (see also Causes; Diagnosis; glycosylation, 117, 352 Epidemiology; Prevalence; phosphorylation, 117, 357 Prevention; Treatment; specific posttranslational modification, 117, 121, diseases) 357 common diseases in developing replacement therapies, 63, 121, 152 countries, 86 Proteomics, 117, 124, 125, 358 defining and tabulating, 16, 24, 32-36, Pseudo-Hurler polydystrophy, 367 85-86, 358 Pseudohypoaldosteronism, 366 effective treatments, 16 PsychoGenics, 381 examples, 17 Public Health Service Act, 78 genotype vs. phenotype rarity, 36 Public-private partnerships and other knowledge base, 42 coordinating strategies impacts on patients, families, and biomarker identification and validation, communities, 41-42, 69-72 157-158, 167, 168 information resources, 33-34 clinical trials, 134 number and variety of, 16, 33, 42-43, Coalition Against Major Diseases, 167, 50, 112 168 number of people affected, 51 Critical Path Initiative, 8, 95, 102, 109, Rare Diseases Act, 25, 51 168, 171, 174, 242 Rare Diseases Clinical Research Network, defined, 138 2, 8, 9, 19, 21, 25, 28, 45, 52, 67, importance, 26 71, 135, 145, 162, 163, 171, 175- neglected tropical diseases model, 176, 365-369 138-139 Rare Diseases Day, 71 NIH programs, 139 Rare Disease Orphan Product Development promoting research, 134 Act, 25 recommendations for strengthening the Rare Kidney Stone Consortium, 369 drug safety system, 101 Recombinant Spinal Muscular Atrophy project, 139 DNA techniques, 121, 351 TRND program, 2, 29, 139, 171, 174 hirudin, 221 Pulmonary artery hypertension, 159, 302, human acid alpha-glucosidase 303, 328, 330 (Myozyme), 329, 332 Pulmonary fibrosis, 49 human bone morphogenetic protein, 214 Pulmonary hyperinflation, 377 n.10 Pure autonomic failure, 365 human growth hormone, 329 Pycnodysostosis, 367 Recommendations assessment of CDER review of applications (3-1), 5, 105-107, 159, Q 244 clinical research networks (5-4), 8-9, Quinine sulfate (Qualaquin), 302 n.27, 175-176, 243, 244 329, 332 clinical trials design and analysis (3-2), 5-6, 107-108, 242, 243, 244 compendium on off-label drug uses (6- R 2), 10, 202-203, 245 coverage and reimbursement (6-1), 10, Rabies, 53 201-202, 245 Radiation-induced diseases, 51, 55 Cures Acceleration Network (5-5), 9, Raloxifene (Evista), 92 n.11, 302, 304 n.31, 176-177, 242, 243, 244 319, 330, 334 data- and resource-sharing platform Rapid Access to Interventional Development (4-1), 6-7, 129, 142-144, 242, 243 (RAID), 139, 169, 171, 174

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 INDEX guidelines for CDER reviewers and Regulation of orphan drugs and biologics sponsors (3-1), 5, 105-107, 244 (see also Approval process for HDE incentives (7-2), 12, 238-239 orphan drugs and biologics; Center integrated research and drug for Drug Evaluation and Research; development strategies, 13-14, 247 Orphan Drug Act; Postmarketing medical device needs assessment (7-1), studies requirements; other specific 11-12, 237-238, 242, 244 statutes) medical device shipment limits (7-3), 12- biologics, 4, 77 n.2, 78, 92, 107, 210, 13, 239, 244 214 n.9 medical device sponsor assistance (7-4), FDA resources and organization, 13, 238, 240, 244, 245 101-105 NIH action plan for rare diseases (4-2), general framework, 75-84 7, 144, 145-146, 164, 242, 243, indications for common conditions and, 245 37 NIH-funded product development study international harmonization, 29 design (3-3), 6, 108-109, 243, off-label use of drugs, 37 245 prevalence data, 44 patient registries and biorepositories recommendations, 5-6, 105-109 (5-3), 8, 129, 175, 242, 244 safety notices, 55 preclinical development service (5-1), treatment use of investigational drugs, 7-8, 173-174, 243, 245 78-79, 60 surrogate endpoint criteria (5-2), 8, 174, trends in designations and approvals, 242, 243, 244 92-93 task force on accelerating rare diseases Regulatory policy incentives (see also R&D (8-1), 14, 242, 247-248 Humanitarian Device Exemption; Registries (see also Patient registries) Marketing exclusivity; Orphan Drug clinical trials, 166 Act) defined, 358 commercial value and, 25 genetic tests, 60 establishing eligibility for, 87-88 Regulation of medical devices (see also fee waivers, 4, 24-25, 26, 30, 79-80, 86, Humanitarian Device Exemption) 87, 217, 292, 309 alternate approval routes, 215-220 generic products, 88-89 basic framework, 209-215 grants for research, 4, 26, 29, 30, 37, clearance process, 210-211, 219, 222, 74, 86, 87, 91, 94, 292, 293 223, 237, 347 guidance for product developers, 26, 30, combination products, 214-215 292 custom device, 222-224, 349 historical context, 2, 22-27 device classification and, 210-212 international comparisons, 29, 30 diagnostic devices, 60, 124, 212 medical devices, 2, 25, 27, 37, 86, in vitro devices, 212 216-222 laboratory-developed tests, 213 orphan drugs, 29, 86-88, 216-220 marketing exclusivity, 11, 208-209, 215, pediatric drugs and devices, 25, 89, 91, 216, 217 220-222 pediatric devices, 220-222 program administration, 90-91 premarket approval application, 11, statutory basis for, 2, 4, 21, 25-26, 37, 211, 215, 216, 217-218, 220 n.13, 74, 85, 292 222, 223, 230, 231, 233, 234, 235, tax credits, 4, 12, 23, 24, 26, 30, 74, 86, 236, 239, 240, 346, 349, 353, 358 87, 216-217, 238, 292, 309, 379 time line, 24-25 Regulatory science, 4, 102, 103, 106, 358

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 INDEX Renal cell carcinoma, 17, 97, 304 n.31, Sensory ataxia neuropathy dysarthria 329, 330 ophthalmoplegia, 368 Repositories (see also Biorepositories) Serono, 299 of animal models, 7, 143 Severe combined immunodeficiency, 121, Research (see Basic research; Clinical 123, 300 n.20, 369 research; Discovery research; Severe primary IGF-1 deficiency, 339 Infrastructure for research; Target Sharing data and resources (see also discovery; Therapeutics discovery) Databases and data resources; Patient translational, 38-39 registries) Research and development (see also Medical Advanced Research Collaboration device R&D; Orphan drug R&D) model, 127, 141, 371 defined, 40 advocacy groups’ initiatives, 137-138 venture philanthropy, 72 animal models, 128 Respiratory syncytial virus, 339, 341 antibodies, 137, 382 Reticular dysgenesis, 16 biological specimens, 27, 45, 58-59, Rett syndrome, 45 n.3, 46 n.4, 131, 134, 137, 143 365, 373-375 biomarker data, 174 Rheumatoid arthritis, 51 chemical compound libraries, 6, 7, 13, Rickets, 63 137, 138, 141-142, 143, 144, 171 Riluzole (Rilutek), 64, 325, 334 clinical data supporting/denying Risk Evaluation and Mitigation Strategy approvals, 83-84, 98, 118, 164-165, (REMS), 79 n.3, 82-83, 298, 306 166-167, 177 Rockefeller Foundation, 138 n.2 conferences, symposia, and workshops, Rocky Mountain spotted fever, 53 334 Roll Back Malaria Partnership, 138 n.2 DNA sequences, 127 Rufinamide (Banzel), 303, 331, 334 disease mechanism data, 7, 118, 140-141 importance, 26-27, 118 S incentives for, 126-127, 141 institutional barriers, 126, 142 Safe Medical Devices Act of 1990, 24, 27, intellectual property issues, 125-126, 206, 215 (see also Humanitarian 140, 142 Device Exemption) investigator-related barriers, 126, 142 Sage Bionetworks, 141 pharmaceutical companies, 167 Sage Commons, 141 precompetitive models, 140-141, 144, Salivary Gland Carcinomas Consortium, 166-167, 171 369 recommendations, 6-7, 129, 142-144, Salla disease, 367 242, 243 Sandhoff disease, 367 Sage Commons, 141 Sanfilippo syndrome, 367 standardization issues, 156 Sarcoidosis, 53, 131 Shire, 45 n.3 Scheie syndrome, 367 Short bowel syndrome, 318, 328, 329 Schindler disease, 367 Sialidosis, 367 Schistosomiasis, 38, 139 Sialuria, 367 Scleroderma, 131, 385, 386 Sickle cell diseases, 16, 28, 42, 44, 45 n.3, Scleroderma Research Foundation, 373, 51, 61 n.16, 64-65, 66-67, 131, 135, 385-386 139, 326 Scope of this study, 3, 30-31 Sickle cell trait, 32, 54 Secretary’s Advisory Committee on Signature molecule, 358 Genetics, Health, and Society, 213 Sitosterolemia, 60, 369 Securities and Exchange Commission, 84 Sjögren-Larsson syndrome, 369

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 INDEX Sly syndrome, 367 Stiff person syndrome, 45 n.3 Small interfering RNAs, 118-119, 359 Sturge-Weber syndrome, 365 Smallpox, 121 Sucrase deficiency, 326 Smith-Lemli-Opitz syndrome, 46 n.4, 127, Sulfa drugs, 17 369 Sulfatase deficiency, 46, 367 Smith-Magenis syndrome, 45 n.3 Surgical treatments, 63-64 Snakebite treatments, 54, 63 Surrogate endpoints, 4, 8, 21, 81, 95, 99, Social Security Act of 1965, 310 107, 109, 156, 157-159, 160, 166- Social Security Administration, 184 167, 174, 175, 233, 240, 242, 243, Social Security Compassionate Allowances 244, 298, 305, 307-308, 359, 364 program, 310-311, 331 Surveillance, Epidemiology, and End Results Social Security Disability Insurance (SSDI), (SEER) program, 46, 47, 48 n.5 71, 183, 184, 310-311 Swiss Agency for Development and Sodium phenylbutyrate, 63 Cooperation, 138 n.2 Somatropin (Genotropin, Humatrope, Systems biology, 102, 103, 118, 136, 359 Norditropin, Nutropin, Protropin, Serostim, Zorbtive), 298, 299, 300 T n.20, 301, 304 n.31, 321, 326, 328, 330, 332, 338, 339, 341 T-cell lymphoblastic lymphoma, 327 Sorafenib (Nexavar), 97, 304 n.31, 329, Tacrolimus, 321, 329, 336 336 Tadalafil (Adcirca), 303 n.29 Sotalol HCl (Betapace), 302, 324, 336 Taenia solium, 326 Sotalol IV (So-Aqueous), 302, 305 n.33 Takayasu’s arteritis, 369 SPARK program, 135-136 Tangier disease, 15 Special Programme for Research and Target discovery (see also Basic research; Training in Tropical Diseases, 138, Infrastructure for research) 169 barriers and constraints, 112, 113-114 Spina bifida, 20, 56 basic research, 111 Spinal muscular atrophy, 379-380 bioinformatics, 117-118, 141 Spinal Muscular Atrophy Foundation, 373, data sharing, 118, 140-141 379-382 epigenetics, 115-116 Spinal Muscular Atrophy project, 139 exome sequencing, 116 Spinocerebellar ataxia, 35, 366 gene expression analysis, 116 Spiration IBV, 221, 235 genetic studies, traditional, 20, 114-117 Spiration, Inc., 235 genome sequencing, 112, 116 Squamous cell carcinoma of the head and metabolomics, 117 neck, 329 modifier genes, 115 Standards/standardization promotion of, 27-29 biomarker validation and application, proteomics, 116-117 174 public-private partnerships, 139 condition-specific codes, 46 sharing disease mechanism data, 7, 118, data collection, 45, 156, 164 140-141 delivery of care, 66 systems biology, 118 diagnostic approaches, 60-61 and treatment of common conditions, Stanford University, 135-136, 230 113 Stem cell therapy/transplants, 62, 63, 64, value of, 15-16, 19, 20, 112, 113 122, 123, 259 TAS Ecarin Clotting Time Test, 212 n.6, Stem cells, defined, 357, 359 221 Sterol and Isoprenoid Diseases Consortium Tax credits, 4, 12, 23, 24, 26, 30, 74, 86, (STAIR), 369 87, 216-217, 238, 292, 309, 379 Stevens-Johnson syndrome, 171

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 INDEX Transforming growth factor β, 113, 118 Tay-Sachs disease, 57, 367 Tetralogy of Fallot, 63, 64, 131 Transfusion-related iron overload, 55 Thalassemia, 57, 67, 169 Translational research Thalidomide (Thalomid), 56-57, 322, 327, bioinformatics, 117, 360 336 defined, 38-39, 360 Therapeutics Development Network, 66 funding, 9, 21, 135-136, 163 n.2, 165, Therapeutics discovery (see also Animal 170, 176 models and studies; Treatment of incentives for, 293 rare diseases) infrastructure, 67, 125, 170, 171 biologics, 120-122 investigator training, 134, 136, 137, combined gene and cell therapy, 123 164, 170 data sharing, 141-142 networks, 58, 170 diagnostic technologies and, 123-125 scope of this study, 31, 284 funding, 130-134 sharing of resources, 242, 243 gene therapy, 122-123 venture philanthropy strategies, 165 high-throughput screening of compound Trastuzumab (Herceptin), 214, 228 n.17 libraries, 119-120, 139, 141-142, Treatment of rare diseases (see also Delivery 352-353 of health care services) lead optimization, 120 biomarkers of response, 161, 166 public-private partnerships, 138-139 curative, 54-55, 63-64, 74, 119, 292- silico modeling, 120 293, 339 stem cell therapy, 122, 123 dimensions of care, 65 value of, 19-20 disease modifying, 42, 62, 64-65 Therapeutics for Rare and Neglected epidemiological significance, 42 Diseases (TRND) program, 2, 29, examples, 62-63 139, 171, 174 genetic diseases, 61-62 Thiamine deficiency, 55 health risks of, 64 Thoracic insufficiency syndrome, 63, 205 information resources, 61 Thrombocythemia, 326, 331 investigational drugs approved for, 78- Thyroid cancer, 47-48, 304 n.31 79, 80 Thyroid hormone replacement, 119 prevention of other disease- or Thyrotropin alfa (Thyrogen), 304 n.31 treatment-related complications, 65 Tinidazole (Tindamax), 302-303, 317, 318, symptomatic and functional therapies, 328, 332 65, 119 Tissue bank (see Biorepositories) Treprostinil (Remodulin), 303 n.29 Tissue engineering, 122, 135, 231, 232, 360 Treprostinil inhalational (Tyvaso), 303 n.30 Topiramate (Topamax), 303, 328, 336 Trisomy 13, 16 Tourette syndrome, 85 Tropheryma whipplei, 63 Tourette Syndrome Association, 26 n.1 Trypanosomiasis (sleeping sickness), 31, Tox21, 156-157 142, 172 n.3 Toxic substances Tryptophan, 54 causes of rare diseases Tuberculosis, 38, 53, 141, 167, 324, 325, prevention of exposure to, 56 327 Tox21 collaboration, 156-157 Tuberous sclerosis, 28, 131 Toxicology studies, 4, 95, 99, 107, 152, Turner syndrome, 131 156-157 Tyrosinemia, 128, 328 Toxoplasmosis, 325 Tysabri, 55 Training and recruitment of investigators, 7, 25, 77 n.2, 133, 134-137, 144-145, 149, 156, 164, 170, 171, 233, 243, 284, 386

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0 INDEX U Von Hippel-Lindau syndrome, 17, 51 von Willebrand’s disease, 324 Ucyclyd, 299 Ulcerative colitis, 340 United Kingdom, 138 n.2, 302-303 W United States Pharmacopoeia, 203, 312, Wegener’s granulomatosis, 369 350 Wegener’s Granulomatosis Association, 70 University of California, Berkeley, 173 Williams-Beuren syndrome, 52 University of Pennsylvania, 67 Wilms tumor, 15 University of Wuerzburg, 381 Wilson’s disease, 318, 323, 326 Upjohn, 299 Wiskott-Aldrich syndrome, 64, 369 Urea cycle disorders, 63, 369 Withdrawal Urea Cycle Disorders Consortium, 369 of devices, 216, 220, 236 U.S. Patent and Trademark Office, 88 of drugs, 81, 83 n.4, 84, 164, 165, 167, 301 V Wolman disease, 366 World Bank, 138 n.2 Vaccination, 42, 55 World Health Organization (WHO), 46, Vaccines, 37, 78, 120, 121, 134, 149-150, 138 n.2, 303 n.29, 330 151, 346 Variegate porphyria, 368 Vasculitis, 45, 52 X Vasculitis Foundations, 70 X-linked adrenoleukodystrophy, 115 Vasculitis Research Consortium, 52, 369 X-linked hypophosphatemic rickets, 63, 65 Ventricular septal defects, 220 n.13 X-linked protoporphyria, 368 Ventricular tachyarrhythmias, 302, 324 Xeroderma pigmentosa, 63 Vertical Expandable Prosthetic Titanium Xerostomia, 325 Rib, 205, 206, 211, 220, 223 n.15, 228, 229, 233 Veterans Health Administration, 184 Z Vitamin D supplementation, 63 Vogt-Spielmeyer disease, 367 Zinc acetate (Galzin), 317, 318, 326, 332 Zymenex A/S, 45 n.3