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Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

IRB approval and monitoring, 11-12, 218-219, 225, 236

origin and overview, 11, 14, 27, 206, 215-216

Orphan Drug Act incentives compared to, 216-220

pediatric devices, 11, 12, 220, 222, 237, 238, 244

profit restriction, 11, 27, 222, 235-236, 237, 238, 244

recommendations, 12-13, 238-240, 244, 245

shipment limits, 12-13, 27, 220 n.13, 237, 239, 244

supporting justifications, 11, 12-13, 27, 44, 215, 233, 239

tumor markers, 360

withdrawal of, 216, 220 n.13, 236

Humanitarian Use Device (HUD), 11-12, 215, 217, 236-237, 240, 253

(see also Medical devices for small populations)

Hunter syndrome, 200, 219, 330, 367

Huntington disease, 22, 24, 26 n.1, 29, 85, 127, 130, 131, 141, 158, 331

Hurler syndrome, 63, 367

Hutchinson-Gilford progeria syndrome, 21, 22

Hyaline membrane disease, 338

Hydroxocobalamin (Cyanokit), 54

Hydroxyurea (Droxia), 65, 326, 334

Hyperammonemia, 299

Hyperbilirubinemia, 133

Hypercalcemia, 328

Hyperimmunoglobulinemia D with periodic fever syndrome, 309

Hyperphenylalaninemia, 331

Hyperphosphatemia, 324

Hypocitraturia, 323

Hypoplastic left heart syndrome, 64

Hypovolemic postural tachycardia syndrome, 365

I

I-cell disease, 367

Iloprost (Ventavis), 303 n.29

Imaging services and technologies, 102, 123, 124, 137, 186, 206, 212, 231

Imatinib mesylate (Gleevec), 68, 112, 118-119, 191, 298, 299-300, 305, 327, 330, 334

Imiglucerase (Cerezyme), 180, 181

Immune globulin (Gamimune N), 331, 332, 338, 341

Immunex Corp., 299

Immunization (see Vaccines; Vaccination)

Implantable cardioverter defibrillator (ICD), 226, 228-229

In vitro

diagnostic devices, 212, 213, 214, 228 n.17, 353, 354

diagnostic mulitvariate index assay, 213 n.8

fertilization, 157

studies, 103, 128, 149

Incentives (see Regulatory policy incentives)

Indian Health Services, 311 n.3

Indications for drugs or devices

(see also Off-label use)

defined, 37, 309 n.1

Medicare-relevant drugs by, 323-331

pediatric drugs by, 338-340

trends in number per drug, 93

Infantile

Batten disease, 367

botulism, 74, 292-293, 339, 341

globoid cell leukodystrophy, 45 n.3

Krabbe disease, 64

-onset Pompe disease, 96, 159

spasms, 200

Infectious diseases

(see also specific diseases and agents)

drug-resistant strains, 38, 42, 53, 86 n.6

genetic susceptibility, 53-54

neglected, 53

Infectious Diseases Society of America, 86 n.6

Inflammatory breast cancer, 34

Informed consent, 58-59

Infrastructure for research

(see also Biomarkers;

Funding;

Patient registries;

Sharing data and resources)

access to negative FDA findings, 164-165

animal models, 6, 7, 115, 116, 120, 121, 125, 127-128, 139, 143, 380-381

basic research and drug discovery, 125-137

biorepositories, 6, 8, 22, 125, 129-130, 144, 159, 160, 161, 170, 175, 242, 284, 347, 375

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

chemical compound libraries, 6, 7, 13, 138, 139, 141-142, 143, 144, 171-172

clinical research 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)

collaborative platforms, 9, 114, 176-177, 242, 243, 244

drug development, 156-165

innovative clinical trial and data analysis strategies, 163-164

investigator training and recruitment, 7, 25, 77 n.2, 133, 134-137, 144-145, 149, 156, 164, 170, 171, 233, 243, 284, 386

recommendations, 8-9, 175-177, 242, 243, 244

Inherited Neuropathies Consortium, 366

InnoCentive, 166

Innovation effects of Orphan Drug Act all drugs approved, 92, 298-301

analysis, 306-308

characteristics of orphan drugs, 92-93, 301-303

clinical trials development process, 303-306

grant-supported projects approved or cleared, 94

method for analyzing impacts, 295-298

for more common vs. less common diseases, 93

overview of, 92-93

prior research on, 292-295

results of analysis, 298-306

Institute for OneWorld Health, 173

Institute of Medicine (IOM), 2, 30, 38, 101, 104, 105, 140, 157, 158, 165, 174, 211, 220 n.14, 229 n.19, 283

Institutional Review Boards (IRBs), 11-12, 13, 163, 211 n.5, 218-219, 225, 236, 240

Insurance (see Coverage and reimbursement)

Intacs, 224 n.16

Integrated national strategy, 18

challenges, 3

clinical trial designs for small populations, 243-244

elements of, 3, 13, 18, 242-246

organizational structures and resources, 245

priority and goal setting, 245-246

progress assessment, 245-246

public and private involvement, 13, 242-243

recommendations, 13-14, 247

rewards and incentives for innovation, 144-145

sharing resources and infrastructure, 13, 143-144, 243

Interagency Task Force on Drugs of Limited Commercial Value, 22, 23, 24

Interferon beta-1a (Avonex), 319, 325, 332

Interleukin-10, 123

International Classification of Diseases, 46

International Committee of Medical Journal Editors, 166

International Federation of Pharmaceutical Manufacturers Associations, 138 n.2

International Fibrodysplasia Ossificans Progressiva Association, 67

International Network of Paediatric Surveillance Units, 46 n.4

International Partnership for Microbicides, 169

International Registry of Acute Aortic Dissections, 129

International Rett Syndrome Foundation, 134, 287, 373-375

International Scientific Conference on Friedreich’s Ataxia, 383

Interstitial cystitis, 326

Intrathecal drug delivery device, 219

Investigational Device Exemption (IDE), 211-212, 216, 219, 235, 353

Investigational New Drug (IND) access to information on, 164, 166-167

application, 75-76, 80, 148, 152

defined, 354

exploratory studies, 153-154

FDA analysis, 297-298

IDE application compared with, 211-212

Medicare coverage for trials, 200, 201

orphan drug designation, 307

preclinical work, 168

pre-IND meetings, 79, 104, 107, 152

registration of clinical trials, 166

years in clinical development and review, 293-294, 304

Ivermectin (Mectizan), 172 n.3

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

J

Jackson Laboratories, 128, 381

Japan, 30, 32, 33

Jeune syndrome, 63, 220

Juvenile rheumatoid arthritis, 115, 135, 304 n.31, 339, 340

K

Kaiser Family Foundation, 197

Kaiser Permanente, 180

Kaposi’s sarcoma, 327

KBG syndrome, 60

Kearns-Sayre syndrome, 368

Keratoconjunctivitis, 318, 323, 324

Keratoconus, 224 n.16

Kinase inhibitors, 112, 118

Kinases, 117, 354, 357

Krabbe disease, 46, 64, 122, 124, 367

L

Label/labeling (see Indications for drugs or devices;

Off-label use)

combination products, 214, 348

defined, 296, 354

drugs, 39, 75, 150, 155, 302, 308

medical devices, 209, 210, 212 n.7, 223, 349

medical foods, 31 n.3

phase III trials and, 39, 155, 348

revision based on postmarketing studies, 150, 308

statutory basis, 75, 209

Lamotrigine (Lamictal), 303, 327, 334

Lead poisoning, 338

Leber congenital amaurosis, 123, 131

Leber hereditary optic neuropathy, 368

Leigh syndrome, 368

Leishmaniases, 37-38, 142

Lemierre’s syndrome, 53

Lennox-Gastaut syndrome, 303, 327, 328, 331, 338

Lepromatous leprosy, 54, 318, 323

Leptomeningeal angiomatosis, 365

Leroy Matthews and Harry Shwachman Awards, 137

Leukemias, 47-48

Leukoencephalopathy, 55, 368

Licenses/licensing arrangements

for research and therapeutics development tools, 381

Liddle syndrome, 15

Lidocaine patch (Lidocaine patch), 319, 327, 334

Lodoxamide tromethamine (Alomide Ophthalmic Solution), 317, 318, 324, 332

Loeys-Dietz syndrome, 113

Losartan, 113, 118, 162

Lymphangioleiomyomatosis, 41

Lysosomal Disease Network, 366

Lysosomal storage disorders, 61, 96, 118, 121, 139

M

Magnesium carbonate (Renacidin Irrigation), 316-317, 318, 324, 332

Malaria, 38, 54, 86, 138, 142, 168-169, 173, 323, 329

Malignant hyperthermia, 48 n.7, 55 n.12

Mannosidosis, 367

March of Dimes, 134

Marfan syndrome, 16, 52-53, 59, 113, 118, 131, 134, 161, 162-163, 176

Marketing exclusivity

comparable drugs from competitors, 89-90

competitive advantage, 11, 86-87, 90, 209, 292

defined, 4, 87, 354

devices, 11, 208-209, 215, 216, 217

eligibility/ineligibility for, 88, 299

exceptions, 89-90

generic versions of brand-name drugs, 88-89, 90, 181, 301

impacts of, 294

international comparisons, 29, 30

legislation to limit, 27

nonorphan drugs, 294

orphan drugs and biologics, 4, 11, 26, 86-90, 181, 208, 216, 217, 292, 294, 295, 301, 303 n.30, 309, 323-331, 338-340

patents and, 74, 87, 88-90, 208, 209, 294

pediatric drugs, 89, 338-340

population criterion and, 43 n.1, 216

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

start dates by drug, 301, 303 n.30, 323-331, 338-340

withdrawal of, 88

Maroteaux-Lamy syndrome, 187, 367

Mass spectrometry, 117, 124, 354

Mastocytosis, 298, 324

Measles, 56, 121

MeCP2 gene, 374-375

Medicaid, 10, 19, 68, 70, 181 n.2, 183, 184-185, 188, 194, 195-197, 199, 201, 202, 225, 310

(see also Centers for Medicare and Medicaid Services;

Coverage and reimbursement)

Medicaid Rebate Program, 196

Medical Device Amendments of 1976, 209

Medical device R&D

(see also Humanitarian Device Exemption)

clinical studies, 11, 231-234

emergence of complex medical devices, 226

HDE effects on innovation, 234-237

incentives for, 2, 12, 27, 86, 216-220

innovation process, 226-231

orphan drug R&D compared to, 207-209, 216-220

Medical devices for small populations

(see also Humanitarian Device Exemption;

Regulation of medical devices)

approvals, 2

defined, 36-37, 354-355

examples of innovations, 232

insurance coverage, 183, 186, 200, 201, 224-225, 310

needs assessment, 11-12, 237-238, 242, 244

orphan drugs compared to, 11, 206-207

recommendations, 11-12, 237-238, 242, 244

Medical Expenditure Panel Survey, 185

Medical foods, 3, 27, 31, 94

Medical products, defined, 36

Medicare

beneficiaries, 310-311

Modernization Act of 2003, 185 n.4

Part A coverage, 185-186, 224, 311, 315

Part B coverage, 10, 185, 186-188, 192-193, 194, 202, 311, 312, 315, 331

Part C (Medicare Advantage plans), 185, 188, 195, 311, 315-316

Medicare Part D coverage

and access to products, 10

analysis of orphan drug coverage, 194-195, 310

assistance programs for beneficiaries, 200

beneficiary financial responsibilities, 10, 188-189

biologics, 188

dual eligibility for Medicaid and Medicare, 196

general structure, 185, 189-190

list of covered orphan drugs, 323-337

and Medicare Advantage Plans, 315-316

methods for analyzing, 313-315

off-label use and, 191-193, 202

orphan drugs, 313-315, 316-319, 323-331

pediatric orphan drugs, 338-342

plans and drug prices, 193-194, 197, 311-316

prices paid by Medicare under, 196

recommendations, 10, 201-202, 245

stand-alone PDPs and MA-PDs, 316-321, 332-337, 341-342

tiered cost sharing structure, 10, 190-191, 195, 312-313, 319, 320, 323-331

utilization management structure, 191, 313, 319-321, 323-331

Medicare Payment Advisory Commission (MedPAC), 10, 187, 188, 194, 202

Medicare Prescription Drug Improvement and Modernization Act of 2003, 187, 311

Medicines for Malaria Venture, 139, 168-169

Medicis Pharmaceutical Corp., 298

MedlinePlus, 55, 382

Medtronic

deep brain stimulator, 229, 237

Melody transcatheter pulmonary valve, 222

Melanocortin-4 receptor deficiency, 131

Membranous nephropathy, 367

Meningioma, 55

Mercury poisoning, 54

Mesothelioma, 54

Metabolemics, 117, 124, 125, 355

Metabolic therapies, 63

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
×

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

Suggested Citation:"Index." Institute of Medicine. 2010. Rare Diseases and Orphan Products: Accelerating Research and Development. Washington, DC: The National Academies Press. doi: 10.17226/12953.
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Rare Diseases and Orphan Products: Accelerating Research and Development Get This Book
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Rare diseases collectively affect millions of Americans of all ages, but developing drugs and medical devices to prevent, diagnose, and treat these conditions is challenging. The Institute of Medicine (IOM) recommends implementing an integrated national strategy to promote rare diseases research and product development.

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