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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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Agriculture, Rural Development, Food and Drug Administration, and Related Agencies Appropriations Act of 2010, 100
Albright hereditary osteodystrophy, 131
Alglucosidase alfa (Myozyme), 96, 159, 198
Allele, defined, 345, 346
Alpers syndrome, 368
Alpha-1 antitrypsin deficiency, 52, 131, 375
Alpha-1 Foundation, 373, 375-377
Alzheimer disease, 15, 141, 147, 167
Amanita phalloides (“death cap” mushroom), 54
Amatoxin poisoning, 54
Ambrisentan (Letairis), 302, 303 n.29, 330, 334
Amebiasis, 318, 323
Amendments to the Patent and Trademark Act of 1980 (Bayh-Dole Act), 114
American Academy of Pediatrics, 68
American Association of Poison Control Centers, 46
American College of Medical Genetics (ACMG), 57-58, 114
American College of Physicians, 68
American Heart Association, 384
American Institute for Medical and Biological Engineering, 230
American Partnership for Eosinophilic Disorders, 287
American Recovery and Reinvestment Act, 131, 132
American Society of Health-System Pharmacists, 199 n.10
American Society of Hematology, 66-67
Aminoglycoside-induced deafness, 368
Aminolevulinate dehydratase deficiency porphyria, 368
Amyloidosis, 131
Amyotrophic lateral sclerosis (ALS), 16, 28, 64, 85, 166, 184, 310, 325
Amyris Biotechnologies, 173
Andersen-Tawil syndrome, 366
Anencephaly, 56
Angelman, Rett, and Prader-Willi Syndromes Consortium, 365
Angelman syndrome, 115-116, 365
Animal models and studies
access to, 6, 7, 128, 139, 143, 380-381
of biologics, 152
carcinogenicity studies, 150
cystic fibrosis, 127
defined, 345, 355
development, 127-128, 380-381
exploratory IND studies, 75, 153
funding for, 132
genetically modified animals, 115, 116, 127-128
Huntington disease, 127
infrastructure for, 127-128
Marfan syndrome, 113, 162
medical devices, 210
naturally occurring diseases, 127
preclinical studies, 120, 149, 150, 152, 153
repositories, 6, 7, 143, 347
spinal muscular atrophy, 380-381
Antibiotics, 43, 53, 86 n.6, 293
Anthracycline, 55
Anthrax, 81
Antibodies, 113, 120, 121, 137, 149-150, 151, 152, 300, 339-340, 346, 380, 382
(see also Monoclonal antibodies)
resources, 382
Aortic aneurysm, 113, 118, 129, 162
Aplastic anemias, 51
Approval process for orphan drugs and biologics
(see also Center for Drug Evaluation and Research;
Investigational New Drug)
accelerated approval, 80, 81, 82, 87, 97, 156, 157
access to clinical data supporting/denying approvals, 83-84, 98, 164-165, 166-167
basics of, 75-77
defined, 346
evidence of safety and efficacy accepted by FDA, 4, 76-77, 95-98
fast track, 80, 81, 87
funding, 26
generic products, 76, 78, 89, 93
guidance for research sponsors, 4, 13, 27, 75-76, 98, 99-100
guidance for reviewers, 6, 27, 98
inconsistencies in FDA reviews, 4-5, 13, 95, 99-100, 158-159
issues/criticisms of, 4, 95-101
medical device approval process compared to, 216-220
neglected tropical disease drugs, 82, 86 n.7
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new indications, 76
priority reviews, 80, 81, 82, 86 n.7, 87, 300
problems with submitted studies, 4, 45, 98-99
recommendations, 4-6, 105-107, 159, 244
response to problems, 100-101
Special Protocol Assessments, 82, 104
speeding and facilitating, 79-82, 86, 92, 101, 155
trends in designations and approvals, 91-92
user fees, 4, 24-25, 26, 30, 79-80, 86, 87, 101, 103, 104, 217, 292, 309
APRT deficiency (dihydroxyadeninuria), 369
Arginase deficiency (hyperargininemia), 369
Argininosuccinate lyase deficiency (argininosuccinic aciduria), 369
Argininosuccinate synthetase deficiency (citrullinemia I), 325, 369
Arsenic poisoning, 54
Artemether-lumefantrine (Coartem), 86
Asbestos, 54, 56
Aspartylglucosaminuria, 366
Atransferrinemia, 16
Australia, 30, 32, 33, 302-303
Autism, 49
Autoimmune autonomic neuropathy, 365
Autonomic Rare Diseases Clinical Research Consortium, 365
Autosomal dominant disorders, 35, 55 n.12, 346
Autosomal recessive disorders, 96, 346
B
Bacterial corneal ulcers, 325
Balamuthia mandrillaris, 53
Balanced Budget Act of 1997, 311
Baroreflex failure, 365
Basic research
(see also Target discovery)
access to biological specimens, 159, 243
alpha-1 antitrypsin deficiency agenda, 376
centers for, 66
collaborations and partnerships, 284
defined, 38
epidemiological studies and, 42
funding, 21, 130-134, 168, 291, 374, 375
incentives for, 293
infrastructure for, 7, 9, 19, 66, 113, 114, 125, 134-135
innovations, 1-2, 6, 20, 109, 111, 112-113, 169, 242, 243
medical devices, 212 n.7, 231
sharing data on, 140
training of researchers, 135, 136, 137
translation of, 118, 120, 148, 149, 161, 168, 169, 176, 248, 375
value of, 6, 40, 62
Batten disease, 367
Bayesian statistical methods, 163-164, 234
Bell Labs, 226
Benzene, 51
Benzoate-phenylacetate (Ucephan, Ammonul), 299
Beriberi, 55
Berns, Scott, 22
Best Pharmaceuticals for Children Act of 2007, 82, 89
Bevacizumab (Avastin), 304 n.31
Bile acid synthetic enzyme deficiencies, 119
Biliary cirrhosis, 326
Bioengineering, 20-21, 230, 231, 346
(see also Medical device R&D)
Bioinformatics, 117-118, 124, 135, 136, 141, 231, 346, 360
Biologics/biological products
carcinogenicity studies, 150
coverage and reimbursement, 181, 183, 187, 188, 189, 192 n.9, 315, 325, 326, 327, 328, 329, 330, 331
definition, 36, 78, 149-150, 346-347
discovery methods, 120-122
examples, 78
generic, 181, 301
immune response, 151, 152
opportunities and obstacles, 121
preclinical studies, 149-150, 151, 152
priority review, 82
protein replacement therapy, 63, 121
regulation, 77 n.2, 78, 107, 210, 214 n.9
trends in approvals, 92-93, 300, 301
wild-type protein, 152
Biologics License Application (BLA), 78, 164, 167, 237 n.20, 297, 300, 301, 346, 347
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Biomarkers
(see also Genetic factors)
and acceleration of research, 8, 124-125, 157
data collection and sharing, 174
defined, 347
examples for rare diseases, 116, 158-159
FDA initiatives, 102, 105, 168, 171
foundation for discovery, 111, 149
innovative discovery approaches, 166-167, 175
knowledge base, 42
NIH Challenge Grants, 158
proteomic and metabolemic studies, 117, 124, 125
public-private partnerships, 157-158, 167, 168
recommendations for effective evaluation of, 158
signature molecule, 358
standards for validation and application, 174
substudy protocol, 175
as surrogate endpoints, 8, 21, 156, 157-158, 166-167, 174, 359, 364
of therapeutic response, 161, 166
uses, 157
validation inadequacies, 4, 8, 99, 174
Biomarkers Consortium, 157-158, 167, 174
Biorepositories, 6, 8, 22, 45, 125, 129-130, 143, 144, 159, 160, 161, 170, 175, 242, 284, 347, 375
Biotin, 17, 119
Biotinidase deficiency, 119
Blepharospasm, 366
Blood-brain barrier, 121-122, 347
Bone marrow or cord blood transplants, 63, 64, 122
Bortezomib, 304 n.31
Bosentan (Tracleer), 302, 303 n.29, 322, 328, 334
Botulinum toxin, 17, 237 n.20
Botulism, 53, 74, 292-293, 339, 341
Botulism immune globulin (BabyBIG), 74, 292-293, 339, 341
Brain arteriovenous malformation, 365
Brain Vascular Malformation Consortium, 365
Breast cancer, 28, 34, 71, 92 n.11, 155, 214, 228 n.17, 302, 304 n.31, 326, 327, 330
Bronchiolitis obliterans, 366
Buprenorphine hydrochloride (Subutex, Buprenex), 92 n.11, 328, 332
Buprenorphine with naloxone (Suboxone), 92 n.11, 328, 332
Bureau of Maternal and Child Health, 132
Burroughs Wellcome Fund, 137
C
Cadmium, 54
California Department of Health Services, 74, 292-293
Campbell, Robert, 205
Cancer Brain Tumor Registry of the United States, 17
Capsaicin (Qutenza), 302 n.27, 304 n.32
Carbamylphosphate synthetase deficiency, 325, 369
Carcinogenicity studies, 150-151
Carglumic acid (Carbaglu), 96, 150
Carnitine deficiency, 323
Causes of rare diseases
fetal exposures, 56-57
genetic, 1, 16, 20, 22, 41, 51, 52-53
infectious agents, 1, 16, 41, 51, 53-54
injuries, 55
nutritional deficiencies, 55
toxic agents, 1, 16, 41, 51, 54
treatment related to another disease, 1, 41, 51, 55
Celiac disease, 119
Cell
(see also Stem cell therapy)
differentiation, 122, 128, 349
research, 128
therapy, 122, 135, 347
Center for Biologics Evaluation and Research (CBER), 4, 77 n.2, 78, 107, 210, 214 n.9
Center for Devices and Radiological Health (CDRH), 12-13, 210, 211, 212, 213-214, 216, 220, 222, 234, 238, 239, 240
Center for Drug Evaluation and Research
access to data supporting approvals by, 83-84
Associate Director for Rare Diseases, 4, 91-92 100-101, 105, 106, 149, 246
collaboration with OOPD and NIH, 108
and combination products, 214
funding for, 103, 105
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guidelines/guidance for reviewers and sponsors, 5-6, 77 n.2, 98, 101 n.14, 107, 151, 152, 153
and historical controls in phase II trials, 155
inconsistencies in reviews, 4, 5, 95, 98, 99, 151, 158, 173
Medical Policy Coordinating Committee, 101 n.14
organizational culture, 91, 101
problems with research sponsors, 98, 99
recommendations for, 5-6, 105-107, 108
resource and personnel challenges, 6, 99, 103-104, 105
roles and responsibilities, 4, 75, 78, 91-92, 103
Centers for Disease Control and Prevention (CDC), 17, 36, 46, 54, 58, 67, 102, 133, 246, 247, 376
Centers for Education and Research on Therapeutics, 203
Centers for Medicare and Medicaid Services (CMS;
see also Medicaid;
Medicare), 10, 184 n.3, 185, 186, 188, 189 n.6, 190, 192-193, 194, 201, 202, 225, 311, 312, 313
Central precocious puberty, 338
Cerebrotendinous xanthomatosis (CTX), 83 n.4, 369
Chagas disease, 31, 142
Charcot-Marie-Tooth disease, 366
Charge to committee, 2-3
Chemical compound libraries
defined, 349
high-throughput screening, 119-120, 139, 171-172, 352-353
sharing, 6, 7, 13, 138, 141-142, 143, 144
Chemotherapy, 51
Chenodeoxycholic acid (Chemix, Chenodal), 83 n.4, 93
Chicken pox, 56
Child Health Consortium Oversight Committee, 170
Childhood
(see also Pediatric)
cancers, 34, 162, 338
Children’s Oncology Group (COG), 9, 161, 162, 176
Children’s Tumor Foundation, 67, 287
Chloramphenicol, 51
Cholesterol processing disorders, 15
Chordoma Foundation, 134
Chorus program, 165
Chromium, 54
Chromobacterium violaceum, 53
Chronic Graft Versus Host Disease Consortium, 366
Chronic granulomatous disease, 123, 369
Chronic hepatitis C, 339
Chronic immune (idiopathic) thrombocytopenic purpura, 331
Chronic inflammatory demyelinating polyneuropathy, 331
Chronic, intractable (drug-refractory) primary dystonia, 221, 237 n.20
Chronic lymphocytic leukemia, 48 n.5, 139
Chronic myelogenous/myeloid leukemia (CML), 20, 48 n.5, 63, 111-112, 118, 298, 305, 327, 330
Chronic progressive external ophthalmoplegia, 368
Chronic, severe, treatment-resistant obsessive compulsive disorder, 230
Churg-Strauss syndrome, 309
CINCH (Clinical Investigation of Neurologic Channelopathies), 366
Cinacalcet (Sensipar), 322, 328, 334
Citric acid, 316, 318, 324, 332
Citrin deficiency (citrullinemia II), 369
Clinical and Translational Science Awards, 9, 163 n.2, 170-171, 176
Clinical Data Interchange Standards Consortium, 156
Clinical endpoints, 166, 347
(see also Surrogate endpoints)
Clinical Laboratory Improvement Amendments of 1988, 213
Clinical phenotype, 123, 347
Clinical research
(see also Clinical trials)
alpha-1 antitrypsin deficiency, 376-377
Bayesian statistical methods, 163-164, 234
capacity building strategies, 9
consortia, 2, 19, 22, 23, 25, 28, 91, 104, 141, 145, 156, 161-163, 170, 172, 174, 222, 223, 365-369
(see also specific organizations)
defined, 39-40
effectiveness, 40
efficacy, 40
grants, 37
historical case series, 4
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medical devices, 37, 231-234
toxicology studies, 4, 95, 99, 107, 152
training, 133, 134-137, 164
types, 39
Clinical Research Consortium for Spinocerebellar Ataxias, 366
Clinical trials
active treatment concurrent control, 77, 345
adaptive design strategies, 77, 98, 162, 164, 234, 345
biomarker substudy protocol, 175
characteristics of adequate and well-controlled studies, 76-77
communicating with FDA about, 4, 75-76, 99, 104, 107, 152
costs, 161
defined, 39, 348
dose-comparison concurrent control, 77, 350
education/guidance for sponsors and reviewers, 5, 30, 75-76, 77, 100, 101, 107, 108
funding, 102, 103, 107, 132
generic drugs, 75, 89
good clinical practice principles and guidelines, 154
historical controls, 77, 154, 155, 244, 305, 353
innovative designs and data analysis strategies, 5, 163-164, 175
insurance coverage, 183, 185, 200-201
international harmonization of, 29
negative FDA findings, 83-84, 164-165, 166-167, 177
no treatment concurrent control, 77, 356
noninferiority, 77, 356
number required by FDA, 76, 95, 155
patient registries and, 159, 161
pediatric studies, 82, 89
phase I (safety), 39, 81, 82, 94, 96, 99, 148, 150, 152-154, 297, 298, 305, 307, 308, 348, 384
phase II (proof of concept/efficacy), 4, 39, 81, 82, 94, 96, 148, 152, 154, 155, 298, 305, 307, 348
phase III (regulatory proof), 4, 39, 76, 81, 94, 95, 96, 97, 99, 108, 118, 148, 152, 154-155, 167, 298, 305- 306, 348, 384
phase IV (see Postmarketing studies requirements)
placebo concurrent control, 5, 77, 96, 97, 98, 155, 298, 305, 307, 348, 357
population size constraints, 20, 95, 96-98, 100, 112, 142, 154, 155, 159
recommendations (3-2), 5-6, 107-108, 242, 243, 244
registries, clearinghouses, and databases, 45 n.3, 84, 166, 167
sharing information on results, 83-84, 164-165, 166-167, 177
single-arm, 96, 159, 305
Special Protocol Assessments, 82, 104
surrogate endpoints, 4, 8, 21, 81, 95, 99, 107, 109, 156, 157-159, 160, 166-167, 174, 175, 233, 240, 242, 243, 244, 298, 305, 307-308, 359, 364
training and career development for researchers, 133, 134-137, 144-145, 156, 164
Clofazimine (Lamprene), 317, 318, 323, 332
Clostridium botulinum, 74, 339
Coalition Against Major Diseases, 167, 168
Cochrane Collaboration, 61 n.16
Colchicine (Colcrys), 77, 96-97, 172, 180-181, 302 n.27, 305 n.33
Collagenase clostridium histolyticum (Xiaflex), 37, 97
Columbia University Medical Center Spinal Muscular Atrophy Clinical Research Center, 382
Combination products, 74, 94, 102, 214-215, 219-220, 236, 299, 348
Combined immunodeficiency, 35, 121, 123, 300 n.20, 369
Commission for the Control of Huntington’s Disease and Its Consequences, 23, 24
Committee of the Public Health Service, 24
Committee to Combat Huntington’s Disease, 29
Commotio cordis, 55
Condition, defined, 32
Confetti-like macular atrophy, 35
Congenital diaphragmatic hernia, 131
Congenital disorders of glycosylation, 117
Congenital heart disease, 222
Congenital hypothyroidism, 58, 119
Congenital porphyria, 368
Congressionally Directed Medical Research Programs, 28, 133
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CoQ deficiency, 368
Coronary artery disease, 113
Coverage and reimbursement
(see also Medicaid;
Medicare)
Affordable Care Act and, 79
biologics, 181, 183, 187, 188, 189, 192 n.9, 315, 325, 326, 327, 328, 329, 330, 331
clinical trials, 183, 185, 200-201
drugs, 10, 184-198, 323-331, 341-342
generic products, 189, 190, 194, 196, 197, 312, 314, 321
Genetic Nondiscrimination Act, 25
genetic tests, 60, 183-184
medical devices, 183, 186, 200, 201, 224-225, 310
off-label use, 10, 26, 191-193, 198, 202-203
pricing of drugs and devices, 9-10, 179, 180-181, 183, 187, 189, 190, 191, 193-194, 196, 197, 198, 199, 201
private health plans, 182, 197-198
recommendations, 10, 201-202, 245
transition from pediatric to adult care and, 68
Critical Path Initiative, 8, 95, 102, 109, 168, 171, 174, 242
Critical Path Institute (C-Path), 168, 169
Critical Path to TB Drug Regimens, 169
Crohn’s disease, 327
Cromolyn sodium (Opticrom), 323
Crotalidae polyvalent immune fab (ovine) (CroFab), 54
Cryopyrin-assisted periodic syndromes, 331
Cryptosporidiosis, 131, 327
Cures Acceleration Network, 9, 170, 172-173, 176, 177, 242
Custom devices, 222-224, 349
Cutaneous sclerosis, 366
Cutaneous T-cell lymphoma, 327, 330
Cyanide poisoning, 54, 63
Cysteamine (Cystagon), 64, 325, 334
Cystic fibrosis, 19-20, 42, 51, 57, 59, 61 n.16, 65, 122, 125, 127, 131, 135, 158, 187, 277, 366, 378
Cystic Fibrosis Foundation (CFF), 29, 61, 66, 129, 133, 134, 137-138, 372, 373, 377, 378
Cystic Fibrosis Foundation Therapeutics, Inc., 162, 378-379
Cystic fibrosis transmembrane conductance regulator, 138
Cystic hydatid disease, 326
Cystine nephrolithiasis, 323
Cystinosis, 64, 325, 366
Cystinosis Foundation, 26 n.1
Cystinuria, 323, 326, 369
D
Dalkon Shield, 209
Dana Foundation, 137
Danon disease, 366
Data exclusivity rules, 88-89, 349
Data sharing (see Sharing data and resources)
Databases and data resources
approved drugs, 139
clinical trial review findings, 83-84, 164-165
generic orphan drugs, 295, 315
OMIM, 34, 35 n.7
orphan drugs, 91
Orphanet, 33-34, 35, 36, 46, 48, 93 n.12
product research grants lists, 94
DeBakey VAD Child Left Ventricular Assist System, 207, 221
Deep brain stimulation devices, 17, 229, 230, 235, 237
Deferasirox (Exjade), 55
Delivery of health care services
comprehensive care centers, 66-67
medical home, 68-69
pediatric-adult care transition, 67-69
physician contacts, 67
Demonstration projects
Dengue fever, 38
Dent’s disease, 369
Department of Defense, 28, 133, 184, 246, 247
Department of Health and Human Services, 22, 57, 84 n.5, 166, 198
(see also specific agencies)
Medicaid Rebate Program, 196
National Commission on Orphan Diseases, 26
Office of the Inspector General, 91, 199 n.11
recommendations for, 14, 174, 247
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Department of Veterans Affairs, 311 n.3
Dermatofibrosarcoma, 299
Dexrazoxane (Totect), 55
Diabetes and deafness (DAD), 368
Diagnosis of rare diseases
(see also Biomarkers)
accuracy and timeliness, 20, 59
companion diagnostic test, 74, 105, 214, 219, 348-349
genetic tests, 57, 58, 60, 124, 125, 183-184, 213, 228 n.17, 283, 351, 382
imaging services and technologies, 102, 123, 124, 137, 186, 206, 212, 231
implanted laboratory-on-a-chip, 232
insurance coverage, 60
newborn screening, 17, 46, 57-59, 64, 117, 124, 125, 377
obstacles to, 59-60
orphan drugs for, 37
phenotyping, 123, 125, 127, 136, 164, 357
regulation of devices for, 124, 212-214
SMN (human) ELISA Kit, 380
standardization of approaches, 60-61
technologies, 123-125
Undiagnosed Diseases Program, 59, 67
Diamond-Blackfan anemia, 64
Dietary avoidance therapy, 119
Dietary supplements, 54 n.10, 56, 63
Dihydropyrimidine dehydrogenase gene mutation, 55 n.12
Discovery research
(see also Acceleration of discovery research;
Infrastructure for research;
Target discovery;
Therapeutics discovery)
basic research and, 19-20, 111
challenges and opportunities, 1, 19-22
historical and policy context, 22-30
innovative platforms, 137-142
organized research on exceptionally rare diseases, 22
recommendations, 142-146
time line of policy-related events, 24-25
Disease, defined, 32
Disorder, defined, 32
DNA
analysis tools, 112
methylation, 115-116, 349, 355
modification, 115-116, 124, 349
repositories, 22, 127, 347, 375
sequencing, 116, 125, 127, 349-350
Dopamine beta hydroxylase deficiency, 365
Dornase alfa (Pulmozyme), 187
Doxorubicin liposome (Doxil), 304 n.31, 327, 332
Drug delivery innovations, 232
Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act), 88
Drug-resistant strains of infectious diseases, 38, 42, 53
Drugs
(see also Orphan drugs)
defined, 36, 350
off-label use, 37
Drugs for Neglected Diseases, 141
Druker, Brian, 111, 112
Duchenne muscular dystrophy, 52, 59, 63, 113, 131
Dupuytren contracture, 37, 97
Dystonia Coalition, 366
Dystonia Medical Research Foundation, 26 n.1
Dystonias, 17, 221, 366
E
Economic costs of rare diseases, 69-70
Effectiveness, defined, 40, 350
Efficacy, defined, 40, 350
Eflornithine (Vaniqa), 172 n.3
Ehlers-Danlos syndrome, 130, 131
Electronic health records, 46, 66
Eli Lilly and Company, 141, 142, 165-166, 299
Emphysema, 235
Encephalomyopathy, 368
Encephalopathy, 133, 368
End-of-life care, 65
End-stage heart disease, 218 n.12, 221
End-stage renal disease, 184, 310, 324
Endpoint
(see also Clinical endpoints;
Surrogate endpoints)
defined, 350
Enlight Biosciences, 140-141
Environmental modification/adaptation, 63
Environmental Protection Agency, 156
Enzo Life Sciences Inc., 380
Enzyme replacement therapy, 62, 63, 64, 78, 88, 96, 121-122, 150, 300, 328
Eosinophilia-myalgia syndrome, 54
Eosinophilic leukemia, 298
Epicel (cultured epidermal autografts), 221
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Epidemiology of rare diseases
(see also Prevalence of rare diseases)
condition-specific codes, 46
factors affecting data, 42
genotype-phenotype correlations, 45, 36 n.4
incidence rates, 17, 43, 44, 45-46, 47-48, 49, 57, 128, 215-216, 353, 358
national data collection programs, 45-46
natural history studies, 4, 6, 22, 42, 44-45, 71, 98, 99, 128, 132, 135, 145, 159, 244, 353, 376-377
newborn screening programs, 46
objectives of epidemiologic research, 42, 44
policy uses of data, 44
prevalence data, 1, 17, 47-51
single-disease studies, 45
sources of data, 45-46
Epigenetics, 15, 44, 115-116, 118, 124, 125, 155, 350
Episodic ataxias, 366
Erythema nodosum leprosum, 56, 318, 323, 327
Erythropoietic protoporphyria, 368
Ethical issues, 44, 55, 57, 77 n.2, 125, 234-235, 377
European Medicines Agency, 29, 48 n.8, 168
European Rare Diseases Therapeutic Initiative, 142
European Union
coding of rare diseases, 46
definition of rare disease, 32, 33, 34, 47
EPPOSI workshop on patient registries, 160
Orphanet, 33-34, 35, 36, 46, 48, 93 n.12
policy incentives for orphan drug development, 29, 30
prevalence of rare diseases, 33-34, 48, 93 n.12
survey of rare diseases, 59
Treat-NMD Clinical Research Initiatives, 382
Exome sequencing, 116, 124, 125, 349-350
F
Fabry disease, 46, 121, 366
Familial bilateral striatal necrosis (FBSN), 368
Familial breast cancer, 33
Familial cavernous malformations, 365
Familial dilated cardiomyopathy, 131
Familial dysautonomia, 57
Familial hypercholesterolemia, 113
Familial Mediterranean fever, 35 n.7, 96-97, 180
Fanconi anemia, 15, 51, 52, 122, 131, 132
Fanconi Anemia Research Fund, 133, 286
Farber’s syndrome, 46, 367
FasterCures, 372
Federal Food, Drug, and Cosmetic Act, 75, 77, 78, 96, 180, 209, 302 n.27, 347, 354
Fee waivers, 4, 24-25, 26, 30, 79-80, 86, 87, 217, 292, 309
Felbamate (Felbatol), 303, 338, 342
Fibrodysplasia ossificans progressiva (FOP), 47, 67, 287
First Data Bank, 315, 318
Fludarabine phosphate (oral), 90
5-Fluorouracil, 55 n.12
Focal and segmental glomerulosclerosis, 367
Folic acid supplementation, 56
Food and Drug Administration, 2, 376
(see also Approval process for orphan drugs and biologics;
Center for Biologics Evaluation and Research;
Center for Drug Evaluation and Research;
Regulation of orphan drugs and biologics)
Advancing Regulatory Science Initiative, 102, 103
agency-wide concerns, 101-103
complexity of work of, 73
Critical Path Initiative, 8, 95, 102, 109, 168, 171, 174, 242
grants program for orphan products, 4, 133
guidance on animal carcinogenicity studies, 150, 151
interagency collaborations, 156
international initiatives, 29
Medical Device Reporting system, 219
Neurologic Drugs Advisory Committee, 23
NIH-FDA Leadership Council, 106
Office of Combination Products, 214
Office of Orphan Products Development, 28, 30, 87, 88, 90-91, 92, 100, 101, 104-105, 108, 109, 172, 206, 210, 215, 220, 222, 292-293, 295, 372
referral of grant applications to NIH, 109
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repurposing existing drugs, 171-172
resources and organization, 4, 27, 79-80, 101-105
statutory authority, 75
“transparency” initiative, 84, 166-167
Food and Drug Administration Amendments Act, 25, 84, 109, 166
Food and Drug Administration Modernization Act of 1997, 76, 84, 87, 89, 156, 166
Forced expiratory volume, 158-159
Foundation for the National Institutes of Health, 157-158, 167, 174
Fragile X syndrome, 57, 287
Freedom of Information Act, 83 n.4, 302 n.23, 304 n.31
Friedreich’s ataxia, 52, 169, 382-383
Friedreich’s Ataxia Research Alliance, 128, 373, 382-384
Frontotemporal dementia, 373
Fucosidosis, 367
Fujirebio Mesomark Assay, 212 n.6
Funding
advocacy groups and foundations, 28, 29, 132, 133-134, 141, 172-173
animal model development, 127-128
basic research, 21, 130-134, 168, 291, 374, 375
for biomedical research, by source, 28
clinical research consortia, 161-162
clinical trials, 102, 103, 107, 132
commercial sources, 28, 29
epidemiological data and, 44
FDA grants under HDE, 4, 26, 29, 30, 37, 74, 86, 87, 91, 94
foreign governments, 134
inadequacies, 156
information sharing tied to, 127, 141
landscape analysis, 374
NIH and other federal agencies, 21, 27, 28, 102, 103, 127, 130-133, 134, 161-162, 172-173
orphan products grants program, 6, 12, 94, 108-109
preclinical research, 132
prevalence of disease and, 130-132
tracking and coordinating, 27
training of researchers, 135, 136, 137, 144-145
young investigator awards, 137
Fusobacterium necrophorum, 53
G
Galactosemia, 64
Galactosialidosis, 367
Galsulfase (Naglazyme), 150, 187
Gangliosidosis, 367
Gastric cancer, 131
Gastrointestinal stromal tumor, 61, 298
Gates Foundation, 173
Gaucher disease, 46, 63, 64, 121, 180, 328, 367
Gemtuzumab ozogamicin for injection (Mylotarg), 81
GenBank, 127
Gene, defined, 350
Gene expression
analysis/profiling, 116, 117, 124, 125, 351
defined, 350-351
Gene mapping, 114-115, 351
Gene products, 62, 114, 351
Gene therapy/transfer, 62, 63, 122-123, 135, 351, 377, 379
Gene transcription, 116, 349, 350-351, 355, 360
GeneClinics, 382
Genentech, 299
Generic orphan products
approval process, 76, 78, 89, 93
availability, 93, 181, 296, 301, 315, 321, 323-327, 329
biologics, 181, 301
challenges to innovator patents, 89 n.9
clinical trials, 75, 89
competitiveness, 10, 181, 301, 303 n.28
databases, 295, 315
exclusivity rules and, 88-89, 90, 181, 301
incentives for development, 88-89
insurance coverage, 189, 190, 194, 196, 197, 312, 314, 321
market share for orphan drugs, 93
new orphan drug approval for discontinued drugs, 93
pricing, 181, 190, 196, 197
public availability of FDA review, 83
GeneTests, 60, 382
Genetic Alliance, 42, 70, 284, 372
Genetic Alliance Biobank, 129
Genetic and Rare Diseases Information Center, 33
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Genetic Disorders of Mucociliary Clearance, 366
Genetic factors
autosomal dominant disorders, 35, 55 n.12, 346
autosomal recessive disorders, 96, 346
causes of disease, 52-53
chance mutations, 53-54
microarray methods, 116
multiple-gene, 53, 115
mutations, 16, 22, 36, 51, 52-53, 55 n.12, 60, 113, 115, 118, 123, 124, 130-131, 214, 355, 356, 365, 373-374, 381
pharmacogenetics, 124
scientific and technical advances, 54
screening and counseling programs, 57, 58, 65
single-gene defects, 22, 52
susceptibility to infectious diseases, 53-54, 116
traditional genetic studies, 20, 114-117
variants of diseases, 52
Genetic Information Nondiscrimation Act of 2008, 25, 70, 71
Genetic tests/testing, 57, 58, 60, 124, 125, 183-184, 213, 228 n.17, 283, 351, 382
Genome
defined, 351
sequencing, 112, 116, 124, 125
Genome-wide association studies, 115, 352
Genomics Portal, 141
Genotype, 36, 45, 46 n.4, 58, 128, 248, 352, 357
Genotyping, 124, 127, 352
Genzyme, 45 n.3
Giant cell (temporal) arteritis, 369
Giardiasis, 302-303, 318, 328
Glatiramer acetate (Copaxone), 322, 326, 334
GlaxoSmithKline, 142
Glioblastoma multiformae, 17, 304 n.31
Global Forum for Health Research, 138 n.2
Glucono-delta-lactone, 316, 318, 324, 332
Glutamine (Nutrestore), 317, 318, 329, 332
Gordon, Leslie, 22
Gorham’s disease, 52
Government Accountability Office (GAO), 81, 157, 180, 190-191, 222, 238, 308
Graft versus host disease, 122, 366
H
H1N1 virus, 228 n.17
Hamburg, Margaret, 73
Heartsbreath test, 212 n.6
Hemochromatosis, 32, 36, 63
Hemophilia, 67, 121, 122, 127, 324
Hepatitis, 51
Hepatocellular carcinoma, 97, 304 n.31
Hepatocerebral disease, 368
Hepatoerythropoietic porphyria, 368
Herbal supplements, 54
Hereditary
coproporphyria, 368
hemorrhagic telangiectasia, 45 n.3, 365
inclusion body myopathy, 139
spherocytosis, 65, 131
tyrosinemia type 1, 128, 328
Herpes virus, 51
Histones, 115-116, 125, 353
Histrelin acetate (Supprelin LA), 90, 338, 341
HIV/AIDS, 42, 81, 169, 189, 228, 300, 312, 323, 324, 326, 327, 338
Holocarboxylase synthetase deficiency, 17
Homeopathic Pharmacopoeia of the United States, 350
Homocystinuria, 326
Hookworm, 139
Human genome sequencing, 112
Human growth hormone, 93, 298, 299, 318, 329
(see also Somatropin)
Humanitarian Device Exemption (HDE)
administration, 91, 210
approvals, 218, 220, 222, 237
clinical studies, 11, 212, 217, 223 n.13, 236
combination products, 214, 236, 237 n.20
comparable devices, 216, 217
coverage and reimbursement, 66, 218, 224-225
defined, 253
diagnostic devices, 215
eligibility, 11, 215-216, 238
examples of approved devices, 211, 212, 221, 230, 235, 237
guidance and assistance for device sponsors, 13, 219, 238, 240, 244, 245
incentives offered by, 11, 12, 27, 86, 208-209, 216-220, 238-239
and innovation, 234-237, 283
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Metachromatic leukodystrophy, 45 n.3, 46, 367
Metronidazole topical (Metrogel), 317, 318, 323, 332
Mevalonic aciduria, 369
Microarray methods, 116, 230, 351, 355
Microfluidic devices, 124
MicroRNAs (miRNAs), 116, 355
Microscopic polyangiitis, 369
Midodrine (ProAmantine), 308, 326, 334
Milk thistle extract, 54
Miniaturization, 226, 232
Minimal change disease, 367
Mitochondrial
Complexes I–V deficiencies, 368
DNA depletion syndrome, 368
encephalopathy lactic acidosis, 368
neurogastrointestinal encephalomyopathy, 368
Modafinil (Provigil), 319, 327, 334
Modifier gene, 52, 115-116, 125, 355, 376
Monoclonal antibodies, 78, 118, 213, 300, 355
Morquio syndrome, 367
Mouse models (see Animal models and studies)
Mucoepidermoid carcinoma, 369
Mucolipidosis, 367
Mucopolysaccharidosis, 45 n.3, 121, 330, 367
Multiple myeloma, 56, 141, 180, 200, 304 n.31
Multiple Myeloma Research Consortium, 141, 162
Multiple Myeloma Research Foundation, 372
Multiple respiratory chain enzyme deficiencies, 368
Multiple sclerosis, 55, 324, 325, 326, 371
Multiple sulfatase deficiency, 367
Multiple system atrophy, 365
Muscular dystrophy, 28, 52, 59, 63, 85, 113, 131, 135, 226
Muscular Dystrophy Association (MDA), 168, 372, 384
Mycobacterium avium complex disease, 324
Myelin Repair Foundation, 127, 141, 371
Myelodysplastic syndromes, 329
Myeloproliferative disease, 298-299
Myoclonus, 85, 368
N
N-Acetylglutamate synthase deficiency, 96, 369
Naegleria fowleri, 53
Nanotechnology, 102, 124, 231, 232
Narcolepsy (cataplexy), 131, 327, 328
National Cancer Institute
animal models, 128
Children’s Oncology Group, 9, 161, 162, 176
definition of rare cancers, 48 n.6
SEER program, 46, 47, 48 n.5
National Center for Biotechnology Information, 60, 126-127
National Center for Research Resources, 170
National Chemical Genome Center, 171-172
National Commission on Orphan Diseases, 24, 26, 59
National Disease Research Interchange, 129
National Drug Code, 314 n.10, 315
National Formulary, 209, 350, 354
National Foundation for Infantile Paralysis, 134
National Health Council, 376
National Heart, Lung, and Blood Institute, 45, 66, 134, 162, 230-231
National Human Genome Research Institute, 33
National Huntington’s Disease Association, 26 n.1
National Institute of Biomedical Imaging and Bioengineering, 231
National Institute of Neurological Disorders and Stroke (NINDS), 139, 382
National Institutes of Health
(see also Office of Rare Diseases Research;
individual centers and institutes), 376
action plan for rare diseases (recommended), 7, 144, 145-146, 164, 242, 243, 245-245
Biomarkers Consortium, 157-158, 167, 174
career development awards, 137
Center for Scientific Review, 145
Challenge Grants, 158
Chemical Genomics Center, 139
Child Health Consortium Oversight Committee, 170
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Clinical and Translational Science Awards, 9, 136, 163 n.2, 170-171, 176
data/resource sharing initiatives, 6-7, 127, 129, 142-144, 173-174
design of product development studies, 6, 108-109, 243, 245
Director’s Pioneer Awards, 145
FDA-NIH coordination/cooperation, 5-6, 9, 12, 27, 74, 98, 108, 145, 156, 223
FDA referral of grant applications to, 109
funding for rare diseases research, 27, 45 n.3, 130-133, 134, 136, 137, 149, 203, 374
GenBank, 127
and integrated national strategy, 242, 247
interagency collaborations, 156
natural history studies, 45 n.3
Newborn Screening Translational Research Network, 58
NIH-FDA Leadership Council, 106
Pathway to Independence awards, 144
preclinical development service, 7-8, 173-174, 243, 245
RAID program, 139, 169-170, 171, 174
Rare Diseases Clinical Research Network, 2, 8, 9, 19, 21, 25, 28, 45, 52, 67, 71, 135, 145, 162, 163, 171, 175-176, 365-369
recommendations for, 6-8, 108-109, 129, 142-144, 145-146, 164, 173-174, 242, 243, 245
RePORTER database, 130
resource allocations, 20-21
review mechanisms for rare diseases research proposals, 135, 145, 163
Roadmap, 139, 169
Small Business Innovation Research program, 173
National Marfan Association, 26 n.1, 134
National Neurofibromatosis Foundation, 26 n.1
National Organization for Rare Disorders (NORD), 24, 26, 34, 42, 61, 70, 71, 199-200, 206, 284, 310, 313, 318, 372
National Rare Disease Biospecimen Resource, 129
National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC), 129
National Toxicology Program, 150
Natural history studies, 4, 6, 22, 42, 44-45, 71, 98, 99, 128, 132, 135, 145, 159, 164, 244, 353, 376-377
Neglected diseases
(see also specific diseases)
defined, 37-38, 356
FDA review group, 100
innovation platforms, 165, 168-169, 243
international efforts, 53, 172 n.3, 243
NIH program, 139
priority review vouchers for, 82
public-private partnerships, 138, 139, 142, 149, 168-169
sharing resources, 141-142, 173
training of investigators, 136
TRND program, 2, 29, 139, 171, 174
tropical diseases, 3, 31, 37-38, 82, 138, 149
NeoGram Amino Acids and Acylcarnitine Tandem Mass Spectrometry Kit, 210 n.4
Nephropathic cystinosis, 64, 325
Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE), 367
Netherlands, 138 n.2
Neural tube defects, 56
Neurofibromatosis, 26 n.1, 28, 44, 45, 131
Neurofibromatosis Clinic Network, 67
Neuronal ceroid lipofuscinosis, 63
Neuropathy, ataxia and retinitis pigmentosa syndrome, 368
New Drug Application (NDA), 81, 86, 89, 91, 93, 99, 104, 148, 155, 164, 166-167, 180, 217, 294, 297, 300, 301-302, 304, 346, 356
(see also Approval process for orphan drugs and biologics)
abbreviated, 76, 89, 93
supplemental, 76, 302 n.23, 307
New molecular entities (NMEs), 82, 89, 90, 92-93, 97-98, 136, 140, 292, 294, 295, 300, 302, 315
New York Heart Association, 303 n.29
Newborn screening, 17, 46, 57-59, 64, 117, 124, 125, 377
Newborn Screening Translation Research Initiative, 58
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Newborn Screening Translational Research Network, 58
Niemann-Pick disease, 46, 61, 131, 132, 139, 367, 369
Nilotinib (Tasigna), 305, 330, 334
Nocardiosis, 17
Nondystrophic myotonic disorders, 366
Non-Hodgkin lymphoma, 131
Noonan syndrome, 131, 304 n.31, 330
North American Mitochondrial Diseases Consortium, 368
Northern epilepsy, 367
Novo Nordisk, 299
Nucleotide, defined, 356
Nutritional therapies, 63
O
Octreotide acetate (Sandostatin LAR), 90
Off-label use, 10, 26, 37, 191-193, 198, 202-203, 216, 229, 245, 360
(see also Indications for drugs or devices)
Office of Rare Diseases Research, 30, 45
creation of, 24, 25, 27-28, 71
funding and resources, 130, 246
list of rare diseases, 33, 36, 54, 55, 56
mission, 246
partnerships with advocacy groups and foundations, 134, 372
Rare Diseases Clinical Research Network, 2, 8, 9, 19, 21, 25, 28, 45, 52, 67, 71, 135, 145, 162, 163, 171, 175-176, 365-369
recommendations for, 9, 176
and registries and repositories, 160
TRND program, 2, 29, 139, 171, 174
Ohio State University, 381
Onchocerciasis (river blindness), 31, 172 n.3
Online Mendelian Inheritance in Man (OMIM) database, 34, 35 n.7
OP-1 Putty, 214
Organ transplants, 62, 63, 64, 187, 198, 200, 232, 312, 329, 377
Ornithine transcarbamylase deficiency, 325, 369
Ornithine translocase deficiency syndrome, 369
Orphan Drug Act
(see also Humanitarian Device Exemption;
Innovation effects of Orphan Drug Act;
Regulatory policy incentives)
advocacy groups and, 71
amendments, 24, 26
definition of rare disease, 2, 16, 23, 24, 25, 32
enactment, 23, 24
indication definition, 309 n.1
FDA authority, 2, 292
pupose of, 126
Orphan drug R&D
(see also Clinical trials;
Infrastructure for research, drug development;
Regulatory policy incentives;
specific products)
advocacy group models, 168
biologics, 149-150, 151, 152
chemistry, manufacturing, and controls information, 151
costs, 73-74, 147, 151
current good manufacturing practice, 151
defined, 40
FDA programs, 8, 95, 102, 109, 168, 171-172, 174, 242
foreign and international initiatives, 29-30
funding, 23, 172-173
good laboratory practice, 151
grants, 6, 94
industry models, 165-168
innovative platforms for, 165-173
medical device R&D compared to, 207-209
NIH programs, 149, 169-171
outsourcing, 165-166
preclinical research, 7-8, 81, 149-152
precompetitive models, 140-141, 144, 166-167
process, 147-148
public-private partnerships, 167, 168-169
recommendations, 7-9, 173-177
by state agencies, 74
Orphan drugs
(see also Approval process for orphan drug and biologics;
Infrastructure for research, drug development;
Orphan drug R&D;
specific drugs)
approvals by FDA, 2, 21, 92-93, 147-148
compendium of off-label uses, 10
database, 91
defined, 37
mechanism of action unclear, 64-65
medical devices compared to, 206-207
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Medicare-relevant drugs by exclusivity date and indication, 323-331
small-molecule compounds, 62, 63, 90 n.10, 120, 149, 151, 156, 181, 208, 228, 300, 377
types of drugs approved, 93
Orphan medical products
(see also Medical devices for small populations)
defined, 37
development challenges, 16
Orphanet, 33-34, 35, 36, 46, 48, 93 n.12
Osteogenesis impefecta, 123
Osteoporosis, 302, 304 n.31
Osteoporosis-pseudoglioma syndrome, 113
Ovarian cancer, 16, 28, 44, 324, 327
P
Paget Disease Foundation, 26 n.1
Pancreatic cancer, 47-48, 200
Pancreatic Cancer Action Network, 287
Parenchymal neurocysticercosis, 326
Parkinson disease, 167, 230, 324, 328
Parkinson’s Disease Foundation, 26 n.1
Paroxysmal nocturnal hemoglobinuria, 64, 200
Patent ductus arteriosus, 340
Patent foramen ovale, 220 n.13
Patents, 23, 60
cost considerations, 126
and data sharing, 126
and generic drugs, 88-89, 90, 181
on genes and proteins, 126
licensing, 209, 381
market exclusivity and, 74, 87, 88-90, 208, 209, 294
maximum effective, 294
medical devices, 208, 209, 216
term restoration, 88, 209
Patient Advocate Foundation Co-Pay Relief Program, 200
Patient Protection and Affordable Care Act of 2010, 70, 78, 170, 181, 182, 183, 189, 195-196, 197, 198, 201, 202, 229 n.18, 312 n.4
Patient registries
(see also specific registries)
biorepository links, 159-160
Cancer Brain Tumor Registry, 17
and clinical trials, 159, 161
data sharing, 8, 160, 175
defined, 159
epidemiological studies, 45, 128, 159
fee-based curation, 160
funding for, 246
genetic information combined with, 128
infrastructure capacity building, 125, 129, 149, 156, 160, 284, 375, 382
mandatory participation in, 161
model for, 129
natural history studies, 159, 244
organization of, 128-129
phenotypically related diagnoses, 128-129
postmarketing studies, 83, 96, 159, 298, 306
privacy protection, 160
public-private partnership, 160, 242
recommendations, 8, 129, 175, 242, 244
standardization, 8, 129-130, 143, 144, 160-161, 175
as surrogate endpoints, 159-160, 244
toxic substance exposures, 46
uses, 128-130, 159-161, 244
workshops on, 160
Pearson syndrome, 368
Pediatric
(see also Childhood;
Infantile)
-adult care transition, 67-69
cancers, 15
clinical trials, 82
devices, 11, 12, 25, 220-222, 237, 238, 244
drugs, 89, 338-342
research consortia, 9, 161, 162, 176
Pediatric Heart Network, 134, 162
Pediatric Medical Device Safety and Improvement Act, 25, 222
Pediatric Research Equity Act of 2003, 82
Pegademase bovine (Adagen), 300 n.20
Pentosan polysulfate sodium (Elmiron), 150, 326, 332
Personalized medicine, 20, 202, 248, 351, 356
Pfizer Inc., 142, 170
Pharmaceutical Assets Portal, 170
Pharmaceutical Manufacturers Association, 23
Pharmaceutical Research and Manufacturers of America, 23, 77 n.2, 167
Pharmacia, 299
Pharmacogenomics, 55 n.12, 124, 184 n.3
Phenomics, 124
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Phenotype-genotype correlations, 36, 45, 46 n.4, 128
Phenotypes/phenotypic variation, 36, 44, 51, 113, 115, 129, 143, 357, 359, 381
Phenotypic Drug Discovery Initiative, 142
Phenotyping, 123, 127, 136, 164, 357
Phenylalanine, 63, 158
Phenylketonuria, 20, 63, 68, 158, 331
Phosphate, 63
Phosphine, 54
Pilot projects, 10, 133, 137, 139, 162, 165, 189, 203, 229 n.19, 233
Placebo, defined, 357
Pneumocystis carinii pneumonia, 324
Poisonings, rare, treatment of, 54
Polyarteritis nodosa, 369
Polymorphisms, 116, 124, 125, 352, 357, 358-359
Pompe disease, 96, 121, 159, 198, 329, 367
Porphyria Consortium, 368
Porphyria cutanea tarda, 368
Postmarketing studies/requirements, 148
carcinogenicity studies, 150
defined, 39, 348, 357
difficulty completing, 97-98
examples of approvals with, 96, 97, 212
medical devices, 210, 212
monitoring and reporting requirements, 156, 157
pediatric studies, 82, 96
purpose of and rationale for, 39, 40, 62
registries for, 83, 96, 159, 167, 298, 306
REMS, 79 n.3, 82-83, 298, 306
scope of this study regarding, 31, 39
surrogate endpoints in phase III trials and, 81
trends in requirements for, 298, 305, 307, 308
withdrawal of approval based on, 156
Prader-Willi syndrome, 46 n.4, 48 n.7, 115-116, 339, 365
Preclinical research, 7-8, 40, 81, 89, 95, 100, 107, 108, 120, 128, 132, 139, 145, 146, 147, 148, 149-152, 153, 162, 168, 169, 172, 173, 174, 211-212, 227, 242, 243, 357-358
(see also Animal models and studies;
Basic research)
Predictive Safety Testing Consortium, 168
Premarket approval application, 11, 211, 215, 216, 217-218, 220 n.13, 222, 223, 230, 231, 233, 234, 235, 236, 239, 240, 346, 349, 353, 358
Prescription Drug User Fee Act of 1992, 79
Prevalence of rare diseases
and approvals of orphan drugs, 4-5, 93, 98, 106
and biomarker validation, 157
complete prevalence, 47
data sources, 33-34, 45-46, 48-49, 128, 129, 130
defined, 43, 353, 358
distribution of rare conditions, 1, 48, 49, 93 n.12
documentation to support “orphan” designation, 44, 87, 90-91, 100
estimates for specific diseases, 17, 47, 48 n.7, 180
marketing exclusivity and changes in, 43 n.1, 216
measurement and expression of, 44, 47-48
reliability of data, 43, 48, 50
and research constraints, 112
and resource allocation, 44, 57, 130, 131, 132
thresholds for “rare” definition, 32-33, 34, 47, 85-86, 215-216
Prevention of rare diseases
cost-effectiveness, 58
epidemiological significance, 42
newborn screening programs, 17, 46, 57-59, 64, 117, 124, 125
orphan drugs, 37
primary, 55-57
progressing, 20
secondary, 57-59
tertiary (see Treatment of rare diseases)
Prices/pricing of orphan products, 181, 190, 196, 197
Primary ciliary dyskinesia, 65, 131, 132, 366
Primary hyperoxaluria, 63, 369
Primary Immune Deficiency Treatment Consortium, 368-369
Product development, defined, 40
Progeria, 21, 22, 131, 132
Progeria Research Foundation, 22, 53, 371
Progressive multifocal leukoencephalopathy, 55
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Proteins
glycosylation, 117, 352
phosphorylation, 117, 357
posttranslational modification, 117, 121, 357
replacement therapies, 63, 121, 152
Proteomics, 117, 124, 125, 358
Pseudo-Hurler polydystrophy, 367
Pseudohypoaldosteronism, 366
PsychoGenics, 381
Public Health Service Act, 78
Public-private partnerships and other coordinating strategies
biomarker identification and validation, 157-158, 167, 168
clinical trials, 134
Coalition Against Major Diseases, 167, 168
Critical Path Initiative, 8, 95, 102, 109, 168, 171, 174, 242
defined, 138
importance, 26
neglected tropical diseases model, 138-139
NIH programs, 139
promoting research, 134
recommendations for strengthening the drug safety system, 101
Spinal Muscular Atrophy project, 139
TRND program, 2, 29, 139, 171, 174
Pulmonary artery hypertension, 159, 302, 303, 328, 330
Pulmonary fibrosis, 49
Pulmonary hyperinflation, 377
Pure autonomic failure, 365
Pycnodysostosis, 367
Q
Quinine sulfate (Qualaquin), 302 n.27, 329, 332
R
Rabies, 53
Radiation-induced diseases, 51, 55
Raloxifene (Evista), 92 n.11, 302, 304 n.31, 319, 330, 334
Rapid Access to Interventional Development (RAID), 139, 169, 171, 174
Rare diseases
(see also Causes;
Diagnosis;
Epidemiology;
Prevalence;
Prevention;
Treatment;
specific diseases)
common diseases in developing countries, 86
defining and tabulating, 16, 24, 32-36, 85-86, 358
effective treatments, 16
examples, 17
genotype vs. phenotype rarity, 36
knowledge base, 42
impacts on patients, families, and communities, 41-42, 69-72
information resources, 33-34
number and variety of, 16, 33, 42-43, 50, 112
number of people affected, 51
Rare Diseases Act, 25, 51
Rare Diseases Clinical Research Network, 2, 8, 9, 19, 21, 25, 28, 45, 52, 67, 71, 135, 145, 162, 163, 171, 175-176, 365-369
Rare Diseases Day, 71
Rare Disease Orphan Product Development Act, 25
Rare Kidney Stone Consortium, 369
Recombinant
DNA techniques, 121, 351
hirudin, 221
human acid alpha-glucosidase (Myozyme), 329, 332
human bone morphogenetic protein, 214 n.10
human growth hormone, 329
Recommendations
assessment of CDER review of applications (3-1), 5, 105-107, 159, 244
clinical research networks (5-4), 8-9, 175-176, 243, 244
clinical trials design and analysis (3-2), 5-6, 107-108, 242, 243, 244
compendium on off-label drug uses (6-2), 10, 202-203, 245
coverage and reimbursement (6-1), 10, 201-202, 245
Cures Acceleration Network (5-5), 9, 176-177, 242, 243, 244
data- and resource-sharing platform (4-1), 6-7, 129, 142-144, 242, 243
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guidelines for CDER reviewers and sponsors (3-1), 5, 105-107, 244
HDE incentives (7-2), 12, 238-239
integrated research and drug development strategies, 13-14, 247
medical device needs assessment (7-1), 11-12, 237-238, 242, 244
medical device shipment limits (7-3), 12-13, 239, 244
medical device sponsor assistance (7-4), 13, 238, 240, 244, 245
NIH action plan for rare diseases (4-2), 7, 144, 145-146, 164, 242, 243, 245
NIH-funded product development study design (3-3), 6, 108-109, 243, 245
patient registries and biorepositories (5-3), 8, 129, 175, 242, 244
preclinical development service (5-1), 7-8, 173-174, 243, 245
surrogate endpoint criteria (5-2), 8, 174, 242, 243, 244
task force on accelerating rare diseases R&D (8-1), 14, 242, 247-248
Registries
(see also Patient registries)
clinical trials, 166
defined, 358
genetic tests, 60
Regulation of medical devices
(see also Humanitarian Device Exemption)
alternate approval routes, 215-220
basic framework, 209-215
clearance process, 210-211, 219, 222, 223, 237, 347
combination products, 214-215
custom device, 222-224, 349
device classification and, 210-212
diagnostic devices, 60, 124, 212
in vitro devices, 212
laboratory-developed tests, 213
marketing exclusivity, 11, 208-209, 215, 216, 217
pediatric devices, 220-222
premarket approval application, 11, 211, 215, 216, 217-218, 220 n.13, 222, 223, 230, 231, 233, 234, 235, 236, 239, 240, 346, 349, 353, 358
Regulation of orphan drugs and biologics
(see also Approval process for orphan drugs and biologics;
Center for Drug Evaluation and Research;
Orphan Drug Act;
Postmarketing studies requirements;
other specific statutes)
biologics, 4, 77 n.2, 78, 92, 107, 210, 214 n.9
FDA resources and organization, 101-105
general framework, 75-84
indications for common conditions and, 37
international harmonization, 29
off-label use of drugs, 37
prevalence data, 44
recommendations, 5-6, 105-109
safety notices, 55
treatment use of investigational drugs, 78-79, 60
trends in designations and approvals, 92-93
Regulatory policy incentives
(see also Humanitarian Device Exemption;
Marketing exclusivity;
Orphan Drug Act)
commercial value and, 25
establishing eligibility for, 87-88
fee waivers, 4, 24-25, 26, 30, 79-80, 86, 87, 217, 292, 309
generic products, 88-89
grants for research, 4, 26, 29, 30, 37, 74, 86, 87, 91, 94, 292, 293
guidance for product developers, 26, 30, 292
historical context, 2, 22-27
international comparisons, 29, 30
medical devices, 2, 25, 27, 37, 86, 216-222
orphan drugs, 29, 86-88, 216-220
pediatric drugs and devices, 25, 89, 91, 220-222
program administration, 90-91
statutory basis for, 2, 4, 21, 25-26, 37, 74, 85, 292
tax credits, 4, 12, 23, 24, 26, 30, 74, 86, 87, 216-217, 238, 292, 309, 379
time line, 24-25
Regulatory science, 4, 102, 103, 106, 358
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Renal cell carcinoma, 17, 97, 304 n.31, 329, 330
Repositories
(see also Biorepositories)
of animal models, 7, 143
Research (see Basic research;
Clinical research;
Discovery research;
Infrastructure for research;
Target discovery;
Therapeutics discovery)
translational, 38-39
Research and development
(see also Medical device R&D;
Orphan drug R&D)
defined, 40
venture philanthropy, 72
Respiratory syncytial virus, 339, 341
Reticular dysgenesis, 16
Rett syndrome, 45 n.3, 46 n.4, 131, 134, 365, 373-375
Rheumatoid arthritis, 51
Rickets, 63
Riluzole (Rilutek), 64, 325, 334
Risk Evaluation and Mitigation Strategy (REMS), 79 n.3, 82-83, 298, 306
Rockefeller Foundation, 138 n.2
Rocky Mountain spotted fever, 53
Roll Back Malaria Partnership, 138 n.2
Rufinamide (Banzel), 303, 331, 334
S
Safe Medical Devices Act of 1990, 24, 27, 206, 215
(see also Humanitarian Device Exemption)
Sage Bionetworks, 141
Sage Commons, 141
Salivary Gland Carcinomas Consortium, 369
Salla disease, 367
Sandhoff disease, 367
Sanfilippo syndrome, 367
Sarcoidosis, 53, 131
Scheie syndrome, 367
Schindler disease, 367
Schistosomiasis, 38, 139
Scleroderma, 131, 385, 386
Scleroderma Research Foundation, 373, 385-386
Scope of this study, 3, 30-31
Secretary’s Advisory Committee on Genetics, Health, and Society, 213
Securities and Exchange Commission, 84
Sensory ataxia neuropathy dysarthria ophthalmoplegia, 368
Serono, 299
Severe combined immunodeficiency, 121, 123, 300 n.20, 369
Severe primary IGF-1 deficiency, 339
Sharing data and resources
(see also Databases and data resources;
Patient registries)
Advanced Research Collaboration model, 127, 141, 371
advocacy groups’ initiatives, 137-138
animal models, 128
antibodies, 137, 382
biological specimens, 27, 45, 58-59, 137, 143
biomarker data, 174
chemical compound libraries, 6, 7, 13, 137, 138, 141-142, 143, 144, 171
clinical data supporting/denying approvals, 83-84, 98, 118, 164-165, 166-167, 177
conferences, symposia, and workshops, 334
DNA sequences, 127
disease mechanism data, 7, 118, 140-141
importance, 26-27, 118
incentives for, 126-127, 141
institutional barriers, 126, 142
intellectual property issues, 125-126, 140, 142
investigator-related barriers, 126, 142
pharmaceutical companies, 167
precompetitive models, 140-141, 144, 166-167, 171
recommendations, 6-7, 129, 142-144, 242, 243
Sage Commons, 141
standardization issues, 156
Shire, 45 n.3
Short bowel syndrome, 318, 328, 329
Sialidosis, 367
Sialuria, 367
Sickle cell diseases, 16, 28, 42, 44, 45 n.3, 51, 61 n.16, 64-65, 66-67, 131, 135, 139, 326
Sickle cell trait, 32, 54
Signature molecule, 358
Sitosterolemia, 60, 369
Sjögren-Larsson syndrome, 369
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Sly syndrome, 367
Small interfering RNAs, 118-119, 359
Smallpox, 121
Smith-Lemli-Opitz syndrome, 46 n.4, 127, 369
Smith-Magenis syndrome, 45 n.3
Snakebite treatments, 54, 63
Social Security Act of 1965, 310
Social Security Administration, 184
Social Security Compassionate Allowances program, 310-311, 331
Social Security Disability Insurance (SSDI), 71, 183, 184, 310-311
Sodium phenylbutyrate, 63
Somatropin (Genotropin, Humatrope, Norditropin, Nutropin, Protropin, Serostim, Zorbtive), 298, 299, 300 n.20, 301, 304 n.31, 321, 326, 328, 330, 332, 338, 339, 341
Sorafenib (Nexavar), 97, 304 n.31, 329, 336
Sotalol HCl (Betapace), 302, 324, 336
Sotalol IV (So-Aqueous), 302, 305 n.33
SPARK program, 135-136
Special Programme for Research and Training in Tropical Diseases, 138, 169
Spina bifida, 20, 56
Spinal muscular atrophy, 379-380
Spinal Muscular Atrophy Foundation, 373, 379-382
Spinal Muscular Atrophy project, 139
Spinocerebellar ataxia, 35, 366
Spiration IBV, 221, 235
Spiration, Inc., 235
Squamous cell carcinoma of the head and neck, 329
Standards/standardization
biomarker validation and application, 174
condition-specific codes, 46
data collection, 45, 156, 164
delivery of care, 66
diagnostic approaches, 60-61
Stanford University, 135-136, 230
Stem cell therapy/transplants, 62, 63, 64, 122, 123, 259
Stem cells, defined, 357, 359
Sterol and Isoprenoid Diseases Consortium (STAIR), 369
Stevens-Johnson syndrome, 171
Stiff person syndrome, 45 n.3
Sturge-Weber syndrome, 365
Sucrase deficiency, 326
Sulfa drugs, 17
Sulfatase deficiency, 46, 367
Surgical treatments, 63-64
Surrogate endpoints, 4, 8, 21, 81, 95, 99, 107, 109, 156, 157-159, 160, 166-167, 174, 175, 233, 240, 242, 243, 244, 298, 305, 307-308, 359, 364
Surveillance, Epidemiology, and End Results (SEER) program, 46, 47, 48 n.5
Swiss Agency for Development and Cooperation, 138 n.2
Systems biology, 102, 103, 118, 136, 359
T
T-cell lymphoblastic lymphoma, 327
Tacrolimus, 321, 329, 336
Tadalafil (Adcirca), 303 n.29
Taenia solium, 326
Takayasu’s arteritis, 369
Tangier disease, 15
Target discovery
(see also Basic research;
Infrastructure for research)
barriers and constraints, 112, 113-114
basic research, 111
bioinformatics, 117-118, 141
data sharing, 118, 140-141
epigenetics, 115-116
exome sequencing, 116
gene expression analysis, 116
genetic studies, traditional, 20, 114-117
genome sequencing, 112, 116
metabolomics, 117
modifier genes, 115
promotion of, 27-29
proteomics, 116-117
public-private partnerships, 139
sharing disease mechanism data, 7, 118, 140-141
systems biology, 118
and treatment of common conditions, 113
value of, 15-16, 19, 20, 112, 113
TAS Ecarin Clotting Time Test, 212 n.6, 221
Tax credits, 4, 12, 23, 24, 26, 30, 74, 86, 87, 216-217, 238, 292, 309, 379
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Tay-Sachs disease, 57, 367
Tetralogy of Fallot, 63, 64, 131
Thalassemia, 57, 67, 169
Thalidomide (Thalomid), 56-57, 322, 327, 336
Therapeutics Development Network, 66
Therapeutics discovery
(see also Animal models and studies;
Treatment of rare diseases)
biologics, 120-122
combined gene and cell therapy, 123
data sharing, 141-142
diagnostic technologies and, 123-125
funding, 130-134
gene therapy, 122-123
high-throughput screening of compound libraries, 119-120, 139, 141-142, 352-353
lead optimization, 120
public-private partnerships, 138-139
silico modeling, 120
stem cell therapy, 122, 123
value of, 19-20
Therapeutics for Rare and Neglected Diseases (TRND) program, 2, 29, 139, 171, 174
Thiamine deficiency, 55
Thoracic insufficiency syndrome, 63, 205
Thrombocythemia, 326, 331
Thyroid cancer, 47-48, 304 n.31
Thyroid hormone replacement, 119
Thyrotropin alfa (Thyrogen), 304 n.31
Tinidazole (Tindamax), 302-303, 317, 318, 328, 332
Tissue bank (see Biorepositories)
Tissue engineering, 122, 135, 231, 232, 360
Topiramate (Topamax), 303, 328, 336
Tourette syndrome, 85
Tourette Syndrome Association, 26 n.1
Tox21, 156-157
Toxic substances
causes of rare diseases
prevention of exposure to, 56
Tox21 collaboration, 156-157
Toxicology studies, 4, 95, 99, 107, 152, 156-157
Toxoplasmosis, 325
Training and recruitment of investigators, 7, 25, 77 n.2, 133, 134-137, 144-145, 149, 156, 164, 170, 171, 233, 243, 284, 386
Transforming growth factor β, 113, 118
Transfusion-related iron overload, 55
Translational research
bioinformatics, 117, 360
defined, 38-39, 360
funding, 9, 21, 135-136, 163 n.2, 165, 170, 176
incentives for, 293
infrastructure, 67, 125, 170, 171
investigator training, 134, 136, 137, 164, 170
networks, 58, 170
scope of this study, 31, 284
sharing of resources, 242, 243
venture philanthropy strategies, 165
Trastuzumab (Herceptin), 214, 228 n.17
Treatment of rare diseases
(see also Delivery of health care services)
biomarkers of response, 161, 166
curative, 54-55, 63-64, 74, 119, 292-293, 339
dimensions of care, 65
disease modifying, 42, 62, 64-65
epidemiological significance, 42
examples, 62-63
genetic diseases, 61-62
health risks of, 64
information resources, 61
investigational drugs approved for, 78-79, 80
prevention of other disease- or treatment-related complications, 65
symptomatic and functional therapies, 65, 119
Treprostinil (Remodulin), 303 n.29
Treprostinil inhalational (Tyvaso), 303 n.30
Trisomy 13, 16
Tropheryma whipplei, 63
Trypanosomiasis (sleeping sickness), 31, 142, 172 n.3
Tryptophan, 54
Tuberculosis, 38, 53, 141, 167, 324, 325, 327
Tuberous sclerosis, 28, 131
Turner syndrome, 131
Tyrosinemia, 128, 328
Tysabri, 55
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U
Ucyclyd, 299
Ulcerative colitis, 340
United Kingdom, 138 n.2, 302-303
United States Pharmacopoeia, 203, 312, 350
University of California, Berkeley, 173
University of Pennsylvania, 67
University of Wuerzburg, 381
Upjohn, 299
Urea cycle disorders, 63, 369
Urea Cycle Disorders Consortium, 369
U.S. Patent and Trademark Office, 88
V
Vaccination, 42, 55
Vaccines, 37, 78, 120, 121, 134, 149-150, 151, 346
Variegate porphyria, 368
Vasculitis, 45, 52
Vasculitis Foundations, 70
Vasculitis Research Consortium, 52, 369
Ventricular septal defects, 220 n.13
Ventricular tachyarrhythmias, 302, 324
Vertical Expandable Prosthetic Titanium Rib, 205, 206, 211, 220, 223 n.15, 228, 229, 233
Veterans Health Administration, 184
Vitamin D supplementation, 63
Vogt-Spielmeyer disease, 367
Von Hippel-Lindau syndrome, 17, 51
von Willebrand’s disease, 324
W
Wegener’s granulomatosis, 369
Wegener’s Granulomatosis Association, 70
Williams-Beuren syndrome, 52
Wilms tumor, 15
Wilson’s disease, 318, 323, 326
Wiskott-Aldrich syndrome, 64, 369
Withdrawal
of devices, 216, 220, 236
of drugs, 81, 83 n.4, 84, 164, 165, 167, 301
Wolman disease, 366
World Bank, 138 n.2
World Health Organization (WHO), 46, 138 n.2, 303 n.29, 330
X
X-linked adrenoleukodystrophy, 115
X-linked hypophosphatemic rickets, 63, 65
X-linked protoporphyria, 368
Xeroderma pigmentosa, 63
Xerostomia, 325
Z
Zinc acetate (Galzin), 317, 318, 326, 332
Zymenex A/S, 45 n.3
