D
Glossary, Abbreviations, and Public Laws

GLOSSARY*

Acetylation. Attachment of an acetyl group, a chemical moiety, to a newly translated protein molecule (see also Posttranslational modification). (http://themedicalbiochemistrypage.org/protein-modifications.html)

Active treatment concurrent control. In a clinical trial, “the test drug is compared with known effective therapy.” (21 CFR 314.126)

Adaptive design. A clinical study that “includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study. Analyses of the accumulating study data are performed at prospectively planned timepoints.” (http://www.fda.gov/downloads/Drugs/guidancecomplianceregulatoryinformation/guidances/ucm201790.pdf)

Allele. One of two or more versions of the genetic sequence that comprises a gene, found at a particular location on a chromosome. (Feero et al., 2010). (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=glossary#IX-T)

Animal model. A laboratory animal possessing physical and/or genetic characteristics of a human disease or disorder used for medical research on that condition (see Mouse model). (http://www.genome.gov/glossary.cfm?key=mouse%20model)

*

Consultant Alison Mack assisted with the preparation of the glossary.



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D Glossary, Abbreviations, and Public Laws GLOSSARY* Acetylation. Attachment of an acetyl group, a chemical moiety, to a newly translated protein molecule (see also Posttranslational modification). (http:// themedicalbiochemistrypage.org/protein-modifications.html) Active treatment concurrent control. In a clinical trial, “the test drug is compared with known effective therapy.” (21 CFR 314.126) Adaptive design. A clinical study that “includes a prospectively planned opportunity for modification of one or more specified aspects of the study design and hypotheses based on analysis of data (usually interim data) from subjects in the study. Analyses of the accumulating study data are performed at prospectively planned timepoints.” (http://www.fda.gov/ downloads/Drugs/guidancecomplianceregulatoryinformation/guidances/ ucm201790.pdf) Allele. One of two or more versions of the genetic sequence that comprises a gene, found at a particular location on a chromosome. (Feero et al., 2010). (http:// www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=glossary#IX-T) Animal model. A laboratory animal possessing physical and/or genetic characteristics of a human disease or disorder used for medical research on that condition (see Mouse model). (http://www.genome.gov/glossary. cfm?key=mouse%20model) *Consultant Alison Mack assisted with the preparation of the glossary. 

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 RARE DISEASES AND ORPHAN PRODUCTS Antibody. A protein produced by the immune system that circulates in the blood, where it recognizes foreign substances such as bacteria or viruses, binds to them, and destroys them. (http://www.genome.gov/glossary/index. cfm?id=7) Approval. Authorization by the Food and Drug Administration (FDA) for the marketing of a drug (under a New Drug Application), medical device (under a Premarket Approval Application), or biological product (under a Biologics Licensing Agreement) (see also Clearance; Humanitarian Device Exemption; New Drug Application; Premarket Approval application). Autosomal dominant. A pattern of inheritance that involves a gene located on one of the numbered pairs of autosomal chromosomes (i.e., not the sex chromosomes X or Y) in human cells. Dominant refers to the effect of the specific genetic sequence present at this location (see Allele). An allele is dominant if only one of the paired autosomal chromosomes needs to contain it in order for the person to exhibit the associated trait (see also Autosomal recessive). (http://www.genome.gov/glossary/index.cfm?id=12) Autosomal recessive. A pattern of inheritance that involves a gene located on one of the numbered pairs of autosomal chromosomes (i.e., not the sex chromosomes X or Y) in human cells. Recessive refers to the effect of the specific genetic sequence present at this location (see Allele). An allele is recessive if both of the paired autosomal chromosomes must contain it in order for the person to exhibit the associated trait (see also Autosomal dominant). (http://www.genome.gov/glossary/index.cfm?id=12) Benefit. A positive or valued outcome of an action or event. Biobanking. See Biorepository. Bioengineering. Integration of the physical, chemical, mathematical, and computational sciences with engineering principles for the study of bi- ology, medicine, and behavior. (http://www.nibib.nih.gov/HealthEdu/ ScienceEdu/BioengDef) Bioinformatics. “The application of computers to the collection, organiza- tion, analysis, manipulation, presentation, and sharing of biological data” (see also Translational bioinformatics). (NRC, 2000, p. 4) Biologic or biological product. A “virus, therapeutic serum, toxin, anti- toxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, or arsphenamine or derivative of arsphenamine (or any other trivalent organic arsenic compound), applicable to the preven- tion, treatment, or cure of a disease or condition of human beings.” (42 USC 262(1)) “Biologics can be composed of sugars, proteins, or nucleic

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 APPENDIX D acids or complex combinations of these substances, or may be living en- tities such as cells and tissues. Biologics are isolated from a variety of natural sources—human, animal, or microorganism.” (http://www.fda.gov/ AboutFDA/CentersOffices/CBER/ucm133077.htm) Biologics Licensing Application. Form used by sponsors to request FDA approval to market a new biologic product in the United States based on information about its safety and effectiveness and other requirements. Biomarker. A “characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a[n] . . . intervention” (Biomarkers Definitions Working Group, 2001). Biorepository. A “facility that collects, catalogs, and stores samples of bio- logical material, such as urine, blood, tissue, cells, DNA, RNA, and protein, from humans, animals, or plants for laboratory research. If the samples are from people, medical information may also be stored along with a writ- ten consent to use the samples in laboratory studies.” (http://www.cancer. gov/dictionary/?CdrID=561323) Blood-brain barrier. A“network of blood vessels with closely spaced cells that makes it difficult for potentially toxic substances (such as anticancer drugs) to penetrate the blood vessel walls and enter the brain.” (http://www. cancer.gov/dictionary/?CdrID=46504) Cell therapy. Providing patients with cells (often from the immune system) that function in the treatment of disease or the support of other therapy. (http://www.celltherapysociety.org/index.php/glossarynv/40/160) (http:// www.cancer.gov/dictionary/?CdrID=44024) Chemical library. See Compound library. Clearance. Action taken by FDA under section 510(k) of the Food, Drug, and Cosmetic Act to authorize the marketing of a medical device based on a review of evidence of safety and equivalence to certain previously mar- keted devices; clinical evidence of safety and effectiveness is not usually required. Clinical endpoint. (see also Endpoint). “A characteristic or variable that reflects how a patient [or consumer] feels, functions, or survives.” (Bio- markers Definitions Working Group, 2001) Clinical phenotype. The observable physical and biochemical character- istics of an individual with a specific genetic makeup (see also Pheno- type, Phenotyping). (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book= gene&part=glossary#IX-T)

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 RARE DISEASES AND ORPHAN PRODUCTS Clinical trial. A medical study involving human participants that follows a defined protocol to answer specified questions, for example, about the safety and efficacy of a medical product. Phase I trials initiate the study of candidate drugs in humans. Such tri- als typically assess the safety and tolerability of a drug, routes of adminis- tration and safe dose ranges, and the way the body processes the drug (e.g., how it is absorbed, distributed, metabolized, and excreted). They usually involve less than 100 individuals, often healthy volunteers. Phase II trials continue the assessment of a drug’s safety and dosing but also begin to test efficacy in people with the target disease. These stud- ies may include a range of controls on potential bias, including use of a control group that receives standard treatment or a placebo, the random assignment of research participants to the experimental and control groups, and the concealment (blinding) from participants and researchers of a participant’s assignment. Phase III trials are expanded investigations of safety and efficacy that are intended to allow a fuller assessment of a drug’s benefits and harms and to provide information sufficient to prepare labeling or instructions for the use of the drug. These studies may involve thousands of research participants and multiple sites. Phase IV studies occur after a product is approved for marketing and are highly variable in their design. They are sometimes required by FDA but may be voluntarily undertaken by manufacturers. They are typically intended to provide further information about outcomes in clinical practice, e.g., in broader populations or over longer periods than studied in the trials used to support FDA approval. Combination product. “A product that 1) is comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity; 2) is comprised of two or more separate products packaged together in a single package or as a unit and comprised of drug and device products, device and biological products, or biological and drug products; or 3) is packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where upon approval of the proposed product the labeling of the approved product would need to be changed, e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose.” (21 CFR 3.2(e)) Companion diagnostic test. As defined by FDA, a diagnostic test developed for use with a particular therapeutic product to inform treatment, including

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 APPENDIX D determining which patients are appropriate candidates for the therapy and tailoring decisions about medications. Comparative effectiveness analysis. A systematic evaluation of the evidence on the outcomes of different drugs or other options for treating, preventing, or diagnosing a medical condition Compound library. A collection of small organic molecules organized in a format that facilitates drug discovery and biomedical research, also known as a chemical library. The compounds may be derived from natural sources or synthesized in the laboratory. (http://www.griffith.edu.au/science/ queensland-compound-library/about-us) Computational biology. See Bioinformatics. Custom device. As defined in 21 USC § 360j(b), “a device that: (1) Necessarily deviates from devices generally available or from an applicable performance standard or premarket approval requirement in order to comply with the order of an individual physician or dentist; (2) Is not generally available to, or generally used by, other physicians or dentists; (3) Is not generally available in finished form for purchase or for dis- pensing upon prescription; (4) Is not offered for commercial distribution through labeling or ad- vertising; and (5) Is intended for use by an individual patient named in the order of a physician or dentist, and is to be made in a specific form for that patient, or is intended to meet the special needs of the physician or dentist in the course of professional practice.” Data exclusivity. A period of time during which sponsors of innovative drugs have the exclusive use of the safety and effectiveness data they sub- mitted to obtain FDA approval. (Glover, 2007) Differentiation. Development of immature, unspecialized cells (see Plu- ripotent stem cell) into mature, specialized cells (see also Stem cell). (http:// www.cancer.gov/dictionary/?CdrID=46477) DNA modification. Chemical changes to the DNA such as methylation (see below) that frequently affect gene transcription (see below) and, thereby, gene expression (see below). (http://themedicalbiochemistrypage.org/dna. html#modification) DNA sequencing. Determining the exact order of the base sequence in a segment of DNA, which carries the information that cells use to assemble proteins and RNA (see also Nucleotide). In exome sequencing (see Exome),

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0 RARE DISEASES AND ORPHAN PRODUCTS only the coding regions of the genome are analyzed. (http://www.genome. gov/glossary.cfm?key=DNA%20sequencing) Dose-comparison concurrent control. In a clinical trial, “at least two doses of the drug are compared.” (21 CFR 314.126) Drugs. As defined in 21 USC 321(g)(1): “(A) articles recognized in the of- ficial United States Pharmacopoeia, official Homoeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitiga- tion, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).” Effectiveness. The achievement of desired results in actual clinical practice. Efficacy. The achievement of desired results in controlled clinical studies. Endpoint. “A characteristic or variable that reflects how a patient [or consumer] feels, functions, or survives.” (Biomarkers Definitions Working Group, 2001) Epigenetic. Regulation of gene expression (see below) that occurs without altering the structure of the gene. (Feero et al., 2010) Etiology. Cause or origin of a disease. Exome. Analogous to genome (see below), the complete set of DNA se- quences in a cell that are expressed as proteins. The exome comprises less than 5 percent of the genome. Formulary. “A continually updated list of medications and related in- formation, representing the clinical judgment of physicians, pharmacists, and other experts in the diagnosis, prophylaxis, or treatment of disease and promotion of health.” (http://www.ashp.org/DocLibrary/BestPractices/ FormGdlPTCommFormSyst.aspx) Gene. The basic physical and functional unit of heredity. A gene is a segment of DNA located in a specific position on a particular chromosome. In each gene, the ordered sequence of chemical groups in DNA, called nucleotides (see below), provides a blueprint used by the cell to synthesize a specific functional product, such as a protein. (Feero et al., 2010) (http://www.ncbi. nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=glossary#IX-T) Gene expression. The process by which the information encoded in the DNA sequence of a gene produces a functional molecule, such as a pro- tein or RNA, that operates in the cell. Gene expression encompasses both

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 APPENDIX D gene transcription and gene translation (see below). (http://ghr.nlm.nih. gov/glossary=geneexpression) Gene expression profile. An indicator of the numbers and amounts of all messenger RNAs made in various cell types. This information can be ob- tained using microarray technology (see below). A gene expression profile may be used to find and diagnose a disease or condition and to see how well the body responds to treatment. Gene expression profiles may be used in personalized medicine. (http://www.cancer.gov/dictionary/?CdrID=386201 Gene mapping. The process of establishing the locations of genes on the chromosomes and the distances between them. Early gene maps used link- age analysis, a technique that correlates coinheritance of traits with the physical closeness of their genes on chromosomes. More recently, scientists have used recombinant DNA techniques to establish the actual physical locations of genes on the chromosomes. (http://www.genome.gov/glossary/ index.cfm?id=74) Gene product. RNA or protein produced as a result of gene expression (see above). The amount of gene product is used to measure gene activity, which may be correlated in some cases with disease (see Gene expression profile). (http://ghr.nlm.nih.gov/glossary=geneproduct) Gene transfer. “The insertion of genetic material into a cell.” (http://www. cancer.gov/dictionary/?CdrID=270852) Gene transcription. The process by which cells synthesize a messenger RNA (mRNA) molecule based on, and complementary to, the sequence of DNA in a gene. The mRNA is subsequently translated (see Translation) into pro- tein. (http://ghr.nlm.nih.gov/glossary=transcription) Genetic polymorphism. See Polymorphism. Genetic test. “A genetic test is the analysis of human DNA, RNA, chromo- somes, proteins, or certain metabolites in order to detect alterations related to a heritable disorder. This can be accomplished by directly examining the DNA or RNA that makes up a gene (direct testing), looking at markers co-inherited with a disease-causing gene (linkage testing), assaying certain metabolites (biochemical testing), or examining the chromosomes (cyto- genetic testing).” (http://www.ncbi.nlm.nih.gov/projects/GeneTests/static/ concepts/primer/primerwhatistest.shtm) Genetics. The study of genes and heredity. Genome. The entire set of genetic instructions found in a cell. The human genome consists of 23 pairs of chromosomes in the cell nucleus and a small chromosome found in the mitochondria of cells.

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 RARE DISEASES AND ORPHAN PRODUCTS Genome-wide association studies. “A study that compares the complete DNA of people with a disease or condition to the DNA of people without the disease or condition. These studies find the genes involved in a disease, and may help prevent, diagnose, and treat the disease. Also called GWAS, WGA study, and whole genome association study.” (http://www.cancer. gov/dictionary/?CdrID=636779) Genomics. The study of the complete genetic material of an organism. Genotype. “The genetic constitution of an organism or cell, or the ge- netic sequence at a particular location in the genome” (see Allele). (Feero et al., 2010) (http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book= gene&part=glossary#IX-T) Genotyping. Testing to identify specific genetic sequences (see Allele) in individuals—for example, to determine whether a person with type A blood (see Phenotype) bears one of two possible genotypes: AO (see Heterozygous) or AA (see Homozygous). (http://www.ncbi.nlm.nih. gov/bookshelf/br.fcgi?book=gene&part=glossary#IX-T) Germline. Cells that produce egg or sperm cells. The genetic sequences in parental germline cells are inherited by offspring. (http://www.ncbi.nlm.nih. gov/bookshelf/br.fcgi?book=gene&part=glossary#IX-T) Glycosylation. Attachment of a carbohydrate group to a protein molecule during its synthesis (co-translationally) or immediately afterward (see also Posttranslational modification) to produce a glycoprotein. “Glycopro- teins on cell surfaces are important for communication between cells, for maintaining cell structure and for self-recognition by the immune system.” (http://themedicalbiochemistrypage.org/glycoproteins.html# mechanism) Haplotype. A set of DNA polymorphisms (versions of DNA sequences) that are often inherited together. These polymorphisms may be a combination of alleles (see above) or single-nucleotide polymorphisms (see below), all of which are found on the same chromosome (Feero et al., 2010). Harm. A hurtful or adverse outcome of an action or event, whether tem- porary or permanent. Heterozygous. The inheritance of different forms of a particular gene from each parent (see Allele). A heterozygous genotype contrasts with a homozy- gous (see below) genotype, in which both alleles are identical. (http://www. genome.gov/glossary/index.cfm?id=101) High-throughput screening. A method of drug discovery that permits the si- multaneous testing of large numbers of compounds (see Compound library)

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 APPENDIX D against a particular target. This process typically employs modern robotics, sophisticated control software, advanced liquid handling, and sensitive de- tection methods. Those compounds that prove to be “hits” can be used as the starting point for a drug discovery effort; they are then refined through medicinal chemistry and lower-throughput assays before entering the clinic. (http://www.htscreening.org/) Histone. “A protein that provides structural support to a chromosome. In order for very long DNA molecules to fit into the cell nucleus, they wrap around complexes of histone proteins, giving the chromosome a more com- pact shape. Some variants of histones are associated with the regulation of gene expression.” (http://www.genome.gov/glossary/index.cfm?id=102) Historical control. In a clinical trial, “the results of treatment with the test drug are compared with experience historically derived from the adequately documented natural history of the disease or condition, or from the results of active treatment, in comparable patients or populations.” (21 CFR 314.126) Homozygous. The inheritance of identical forms (see Allele) of a particular gene from each parent (see also Heterozygous). (http://www.genome.gov/ glossary/index.cfm?id=105) Humanitarian Device Exemption. An application required to obtain FDA approval to market a Humanitarian Use Device; similar to a Premarket Ap- proval application except that evidence of efficacy is not required. Humanitarian Use Device. A “medical device intended to benefit patients in the treatment or diagnosis of a disease or condition that affects or is manifested in fewer than 4,000 individuals in the United States per year.” (21 CFR 814.102(a)(5)) Incidence. The number of new cases of a disease or condition during a defined period in a specified population, or the rate at which new events occur in a defined population. In contrast, prevalence (see below) refers to all cases of a disease or condition existing in the population at a given time. (http://ghr.nlm.nih.gov/glossary=incidence) In vitro diagnostic (IVD) devices. IVD devices include reagents, instruments, IVD and systems for use in diagnosing diseases or assessing health. They are used in collecting, preparing, or examining human biological specimens and may be regulated by the FDA as devices and as biologic products. Investigational Device Exemption application. An application to the FDA to approve the legal shipment of a device to be used in a clinical trial when the device has not been approved or cleared for marketing.

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 RARE DISEASES AND ORPHAN PRODUCTS Investigational New Drug application. An application to the FDA to ap- prove the legal shipment of a drug to be used in a clinical trial when the drug has not yet been approved for marketing. Kinase. An enzyme that attaches phosphate groups (see Phosphorylation) to other molecules, which often causes the target molecule to become active. Kinases are part of many cell processes and are the targets of some cancer treatments. (http://ghr.nlm.nih.gov/glossary=kinase) (http://www.cancer. gov/dictionary/?CdrID=641114) Label. As defined in Section 510k of the Food, Drug, and Cosmetic Act, a “display of written, printed, or graphic matter upon the immediate con- tainer of a drug or other product.” Labels often are included within product packaging rather than on the actual product. Lysosome. A membrane-enclosed compartment within a cell containing en- zymes that break down excess or worn-out cell components and also destroy invading viruses and bacteria. If the cell is damaged beyond repair, lysosomes can help it to self-destruct. (http://ghr.nlm.nih.gov/glossary=lysosome) Market exclusivity. As provided for by the Orphan Drug Act, a 7-year period during which the sponsor of an orphan drug has exclusive rights to market the drug for the orphan indication. Mass spectrometry. A technique used to identify chemicals in a substance by their mass and charge. Mass spectrometers are instruments that weigh molecules and measure how much of a compound is present in a mixture. In tandem mass spectrometry, two mass spectrometers are used in series to sort and weigh the molecules in a sample, then break up the molecules (i.e., breaking proteins into amino acids), and sort and weigh their components. (http://www.medterms.com/script/main/art.asp?articlekey=25328) (http:// www.medterms.com/script/main/art.asp?articlekey=25329) Medical device. “An instrument, apparatus, implement, machine, contriv- ance, implant, in vitro reagent, or other similar or related article, including a component, part, or accessory, which is • recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement of them, • intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or • intended to affect the structure or any function of the body of man or other animals, and

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 APPENDIX D which does not achieve any of its primary intended purposes through chemical action within or on the body of man of other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.” (21 USC 321(h)) Metabolomics. The study of the metabolome, “the entire complement of metabolites that are generated in an organism, tissue, or cell type.” (NRC, 2007, p. 14) Methylation. The attachment of methyl groups to DNA at cytosine bases. Methylation is correlated with reduced transcription of genes. (http://www. ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=glossary#IX-T) Microarray technology. A technique used to study the expression of many genes at once. It employs a “gene chip”—a solid surface on which thou- sands of known gene sequences are immobilized in specific locations. When a sample containing DNA or RNA is placed in contact with the gene chip, base pairing between the expressed sequences in the sample and complemen- tary sequences on the gene chip produces light, which allows the expressed sequences in the sample to be identified. (http://www.genome.gov/glossary/ index.cfm?id=125) (http://ghr.nlm.nih.gov/glossary=microarraytechnology) Microfluidic device. “An instrument that uses very small amounts of fluid on a microchip to do certain laboratory tests. A microfluidic device may use body fluids or solutions containing cells or cell parts to diagnose diseases. Also called lab-on-a-chip.” (http://www.cancer.gov/dictionary/?CdrID=561603) MicroRNAs (miRNAs). Small, noncoding RNAs with a broad spectrum of functions, including posttranscriptional regulation of gene expression. (http://www.nature.com/ng/journal/v38/n6s/full/ng1794.html) (http://www. ncbi.nlm.nih.gov/pmc/articles/PMC2605651/) Modifier gene. A secondary gene that influences the expression of a primary gene that in turn controls a physical trait. (http://www.biochem.northwest- ern.edu/holmgren/Glossary/Definitions/Def-M/modifier_gene.html) Monoclonal antibody. An antibody (see above) made in the laboratory to bind specifically to a single type of cell or molecule. Monoclonal antibodies are used to destroy cancer cells directly and to carry toxic substances into tumors. (http://www.cancer.gov/dictionary/) Mouse model. A laboratory mouse that possesses physical and/or genetic characteristics of a human disease or disorder and is used for medical research on that condition. Mouse models may have natural mutations similar to disease-associated human mutations, or they may be created by transferring new genes into mice or by inactivating existing genes (see Ani- mal model). (http://www.genome.gov/glossary.cfm?key=mouse%20model)

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 RARE DISEASES AND ORPHAN PRODUCTS Mutation. A change in a DNA sequence that may or may not affect a physi- cal trait or phenotype (see below). Mutations that occur in eggs or sperm can be passed on to offspring, unlike mutations that occur in body cells (Feero et al., 2010). (http://www.genome.gov/glossary/index.cfm?id=134) Neglected disease. A label often applied to certain tropical infections that are overwhelmingly concentrated in the world’s poorest countries and for which there are inadequate incentives for drug development or inadequate mechanisms to make existing treatments widely available. New Drug Application. Form used by drug sponsors to request FDA ap- proval to market a new pharmaceutical in the United States based on infor- mation about its safety and effectiveness and other requirements. No treatment concurrent control. In a clinical trial, “the test drug is com- pared with no treatment.” (21 CFR 314.126) Noninferiority trials. Clinical trials that involve comparison of an investi- gational product with an active treatment. They seek to demonstrate “that any difference between the two treatments is small enough to allow a conclusion that the new drug has at least some effect or, in many cases, an effect that is not too much smaller than the active control.” (http://www. fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ Guidances/ucm070951.pdf) Nucleotide. The basic chemical building block of RNA and DNA, which are long chains of nucleotides. A nucleotide consists of a sugar mole- cule attached to a phosphate group and a nitrogen-containing base. In DNA, each nucleotide contains one of four bases: adenine (A), cyto- sine (C), guanine (G), and thymine (T). The DNA base sequence carries the information a cell needs to assemble protein and RNA molecules. (http://www.genome.gov/glossary/index.cfm?id=143) (http://www.genome. gov/glossary/index.cfm?id=51) Off-label use. See Unlabeled use. Personalized medicine. An approach to clinical decision making that uses information about an individual’s genetic profile and other characteristics to guide decisions on disease prevention, diagnosis, and treatment. (http:// www.genome.gov/glossary/index.cfm?id=150) Pharmacogenetics. See Pharmacogenomics. Pharmacogenomics. The study of how a person’s genes affect the way he or she responds to drugs. (http://www.cancer.gov/dictionary/?CdrID=631052) Phase I, II, III trials. See Clinical trial.

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 APPENDIX D Phenotype. An organism’s observable characteristics or traits, such as col- oration, size, or the presence or absence of disease. A phenotypic trait may be influenced by genes (genotype), the environment, or both. (http://www. genome.gov/glossary/index.cfm?id=152) Phenotyping. Diagnostic testing in order to infer the genotype (see above) of an individual based on his or her phenotype (see above). (http://www.ncbi. nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=glossary#IX-T) Phosphorylation. The attachment of a phosphate group to a protein by an enzyme known as a kinase (see above). Posttranslational phosphorylation, one of the most common protein modifications that occurs in animal cells, often serves to regulate the protein’s biological activity (see also Posttransla- tional modification). (http://themedicalbiochemistrypage.org/protein-modi- fications.html# phosphorylation) Placebo. “An inactive substance or treatment that looks the same as, and is given the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared to the effects of the placebo.” (http://www.cancer.gov/dictionary/?CdrID=46688) Placebo concurrent control. In a clinical trial, the “test drug is compared with an inactive preparation designed to resemble the test drug as far as possible.” (21 CFR 314.126) Pluripotent stem cell. “A cell that is able to develop into many different types of cells or tissues in the body” (see also Stem cell, Differentiation). (http://www.cancer.gov/dictionary/?CdrID=44797) Polymorphism. Variations in the sequence of a particular gene. The most common of these involve differences in one nucleotide among the thousands that can comprise a gene; these are known as single-nucleotide polymor- phisms (see below). Some polymorphisms involve long stretches of DNA that differ between versions of the same gene. (http://www.genome.gov/ glossary/index.cfm?id=160) Postmarket. Evaluations, activities, and decisions that occur after regulatory approval, clearance, or registration of a medical product for marketing. Posttranslational modification. Enzyme-mediated alterations of newly trans- lated proteins, such as the addition of chemical groups including acetyl (see Acetylation), carbohydrates (see Glycosylation), methyl (see Methylation), or phosphate (see Phosphorylation). (http://walsh.med.harvard.edu/pubs/ PDFs_2/PTM_review.pdf) Preclinical studies. Investigations of toxicity, pharmacological activity, and other characteristics of a promising drug candidate that occurs prior to research with human participants.

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 RARE DISEASES AND ORPHAN PRODUCTS Premarket Approval application. Form used by medical device sponsors to request FDA approval to market certain complex medical devices in the United States based on information about its safety and effectiveness and other requirements. Prevalence. The number of diagnosed cases of a particular condition or disease existing in a specified population at a given time. It is distinct from incidence, which is the number of new cases of the disease arising in the population over a given time period. (http://ghr.nlm.nih.gov/glossary= prevalence) Proteomics. The study of the proteome, the “entire protein complement in a given cell, tissue or organism.” (http://www.nature.com/nature/insights/ 6928.html) Rare disease. In the Orphan Drug Act, a disease or condition that affects fewer than 200,000 people in the United States (21 USC 360bb). Receptor. “A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell.” (http://ghr.nlm.nih.gov/glossary=receptor) Registry. A system for collecting uniform information about a class of individuals or patients who have in common a disease, injury, condition, medical procedure or product, or similar characteristic. Regulatory science. “The development and use of new tools, standards and approaches to more efficiently develop products and to more effectively evaluate product safety, efficacy and quality.” (http://www.fda.gov/News Events/Newsroom/PressAnnouncements/ucm201706.html) Risk. A potential harm or the potential for an action or event to cause harm. Safe. A relative term; “There is reasonable assurance that a device is safe when it can be determined, based upon valid scientific evidence, that the probable benefits to health from use of the device for its intended uses and conditions of use, when accompanied by adequate directions and warnings against unsafe use, outweigh any probable risks” (21 CFR 860.7(d)(1)). Sequencing. See DNA sequencing. Signature molecule. “A biological molecule found in blood, other body flu- ids, or tissues that is a sign of a normal or abnormal process, or of a condi- tion or disease. A signature molecule may be used to see how well the body responds to a treatment for a disease or condition. Also called biomarker and molecular marker.” (http://www.cancer.gov/dictionary/?CdrID=579633) Single-nucleotide polymorphism (SNP). Variant gene sequence that differs by only a single nucleotide. These polymorphisms (see above) occur fre-

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 APPENDIX D quently throughout the human genome; certain SNPs correlate with disease, drug response, and other inherited traits (phenotype; see above). (http:// www.genome.gov/glossary/index.cfm?id=185) Small interfering RNA (siRNA). Short RNA fragment that regulates gene expression and thereby serves as an important mechanism for regulating protein levels in cells. (NRC, 2009, p. 33) Splicing. Process by which noncoding regions are removed from the RNA transcript of a gene and coding regions are joined together to generate mature messenger RNA (mRNA). (http://www.ncbi.nlm.nih. gov/bookshelf/br.fcgi?book=gene&part=glossary#IX-B) Stem cell. “A cell with the potential to form many of the different cell types found in the body. When stem cells divide, they can form more stem cells or other cells that perform specialized functions. Embryonic stem cells have the potential to form a complete individual, whereas adult stem cells can only form certain types of specialized cells. Stem cells continue to divide as long as the individual remains alive.” (http://www.genome.gov/glossary/ index.cfm?id=188) Stem cell transplant. “A method of replacing immature blood-forming cells in the bone marrow that have been destroyed by drugs, radiation, or dis- ease. Stem cells are injected into the patient and make healthy blood cells. A stem cell transplant may be autologous (using a patient’s own stem cells that were saved before treatment), allogeneic (using stem cells donated by some- one who is not an identical twin), or syngeneic (using stem cells donated by an identical twin).” (http://www.cancer.gov/dictionary/?CdrID=46695) Surrogate endpoint (see also Endpoint). “A biomarker that is intended to substitute for a clinical endpoint . . . a surrogate endpoint is expected to predict clinical benefit (or harm or lack of benefit or harm) based on epidemiologic, therapeutic, pathophysiologic, or other scientific evidence. (Biomarkers Definition Working Group, 2001) Surveillance. “The ongoing, systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health” (Guidelines Working Group, 2001). Systems biology. “The science of discovering, modeling, understanding, and ultimately engineering at the molecular level the dynamic relationships be- tween the biological molecules that define living organisms.” (http://www. systemsbiology.org/Systems_Biology_in_Depth) Tissue bank. See Biorepository.

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0 RARE DISEASES AND ORPHAN PRODUCTS Tissue engineering. “The process of creating living, functional tissues to repair or replace tissue or organ function lost due to age, disease, damage, or congenital defects.” This field is also known as regenerative medicine. (http://www.nih.gov/about/researchresultsforthepublic/Regen.pdf) Translation. The process by which cells turn instructions from mRNA tran- scribed from a gene (see Transcription) into chains of amino acids that fold into proteins. (http://ghr.nlm.nih.gov/glossary=translation) Translational bioinformatics. “A field of science in which biology, computer science, and information technology merge into a single discipline to ana- lyze biological information using computers and statistical techniques” (see also Bioinformatics). (http://www.translationalbioinformatics.org/) Translational research. Research that includes two areas of translation. One is the process of applying discoveries generated during research in the laboratory, and in preclinical studies, to the development of trials and studies in humans. The second area concerns research aimed at enhancing the adoption of best practices in the community. (http://grants.nih.gov/ Grants/glossary.html) Tumor marker. A substance present in or produced by a tumor, or by the host in response to a tumor, that can be used for differentiating cancerous from normal tissue. Markers are used in diagnosis, staging, and prognosis of cancer; monitoring effects of therapy; detecting recurrence; localizing tu- mors; and screening in general populations (see also Biomarker). (http://ghr. nlm.nih.gov/glossary=tumormarkers) Unlabeled use. Use of a drug or medical device for a purpose, patient group, or other use that is not specifically approved by the Food and Drug Administration for use as indicated on the product’s label. Such use by physicians is considered part of the practice of medicine, which FDA—by statute—does not regulate. Sometimes described as “off-label” use. Additional Glossary References Biomarkers Definitions Working Group. 2001. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clinical Pharmacology and Therapeutics 69(3):89-95. Feero, W. G., A. E. Guttmacher, and F. S. Collins. 2010. Genomic medicine—an updated primer. New England Journal of Medicine 362(21): 2001-2011. Glover, G. J. 2007. The influence of market exclusivity on drug availability and medical innovations. AAPS Journal 9(3):34. http://www.aapsj. org/articles/aapsj0903/aapsj0903034/aapsj0903034.pdf (accessed Au- gust 20, 2010).

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 APPENDIX D Guidelines Working Group, Center for Disease Control and Prevention. 2001. Updated guidelines for Evaluating Public Health Surveillance Systems. MMWR 50(RR13):1-35. (http://www.cdc.gov/mmwr/preview/ mmwrhtml/rr5013a1.html). NRC. (National Research Council). 2000. Bioinformatics: Converting Data to Knowledge: Workshop Summary. Washington, DC: National Acad- emy Press. NRC. 2007. The New Science of Metagenomics: Revealing the Secrets of Our Microbial Planet. Washington, DC: The National Academies Press. NRC. 2009. A New Biology for the st Century. Washington, DC: The National Academies Press. ABBREVATIONS ACMG American College of Medical Genetics AHRQ Agency for Healthcare Research and Quality ANDA Abbreviated New Drug Application ATSDR Agency for Toxic Substances and Disease Registry BLA Biologics License Application CAN Cures Acceleration Network CBER Center for Biologics Evaluation and Research CDC Centers for Disease Control and Prevention CDER Center for Drug Evaluation and Research CDRH Center for Devices and Radiological Health CFF Cystic Fibrosis Foundation CLIA Clinical Laboratory Improvement Amendments of 1988 CML chronic myelogenous leukemia CMS Centers for Medicare and Medicaid Services COG Children’s Oncology Group C-Path Critical path Institute CTSA Clinical and Translational Science Awards CTX cerebrotendinous xanthomtosis EMEA European Medicines Agency FDA Food and Drug Administration FEV1 forced expiratory volume FMF familial Mediterranean fever FOP fibrodysplasia ossificans progressiva

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 RARE DISEASES AND ORPHAN PRODUCTS GAO Government Accountability Office GenTAC National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions HDE Humanitarian Device Exemption HHS U.S. Department of Health and Human Services ICD International Classification of Diseases ICD implantable cardioverter defibrillator IDE Investigational Device Exemption IND Investigational New Drug IOM Institute of Medicine IRB Institutional Review Board MedPAC Medicare Payment Advisory Commission NAGS N-acetylglutamate synthase NCGC NIH Chemical Genomics Center NCI National Cancer Institute NDA New Drug Application NHLBI National Heart, Lung, and Blood Institute NIH National Institutes of Health NORD National Organization for Rare Disorders OMIM Online Mendelian Inheritance in Man OOPD Office of Orphan Products Development ORDR Office of Rare Diseases Research PHS Public Health Service PMA Premarket Approval application RAID Rapid Access to Interventional Development RDCRN Rare Diseases Clinical Research Network REMS Risk Evaluation and Mitigation Strategy SEER Surveillance, Epidemiology, and End Results SSDI Social Security Disability Insurance TRND Therapeutics for Rare and Neglected Diseases VEPTR Vertical Expandable Prosthetic Titanium Rib WHO World Health Organization

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 APPENDIX D PUBLIC LAWS P.L. 94-295 Medical Device Amendments of 1976 P.L. 97-414 Orphan Drug Act of 1983 P.L. 98-417 Drug Price Competition and Patent Term Restoration Act of 1984 P.L. 101-629 Safe Medical Devices Act of 1990 P.L. 102-571 Prescription Drug User Fee Act of 1992 P.L. 105-115 FDA Modernization Act of 1997 P.L. 108-155 Pediatric Research Equity Act of 2003 P.L. 110-85 Best Pharmaceuticals for Children Act of 2007 (Food and Drug Administration Amendments Act of 2007) P.L. 110-233 Genetic Information Nondiscrimation Act of 2008 P.L. 111-80 Agriculture, Rural Development, Food and Drug Adminis- tration, and Related Agencies Appropriations Act of 2010 P.L. 111-148 Patient Protection and Affordable Care Act of 2010

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