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2 Profile of Rare Diseases After going from doctor to doctor, I tried to think of how the doctors must have felt. . . . This is what I think: “This woman is presenting this odd disease [lymphangioleiomyomatosis] that no one knows how to treat, obviously no cure for, and she and her husband are sitting here looking at me all moon-eyed desperate for help with this dilemma they have been blind-sided with. What am I to do? . . . There simply are no set standards for this, I’m as helpless as she is, yet she has come to me asking for my help.” Nutt, 2007 To have a rare disease is often to have a condition that goes undiag- nosed for years while concerned physicians who have never seen the con- dition before may offer one diagnosis and then search for another when new or advancing symptoms belie the original diagnosis. Once accurately diagnosed, patients with rare conditions may be treated by physicians who have little evidence or guidance to help them—physicians who may expe- rience the frustration imagined by the patient quoted above. Particularly when a condition is extremely rare, patients and families frequently have to travel long distances to consult with the few experts who have experi- ence in treating and studying their rare diseases; patients and their families may even relocate to make access easier. Although the features of specific rare diseases can differ in myriad ways, the effects on life and functioning are often similar and are emotionally and financially devastating for the affected individuals and their families. Patients and family members may 

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 RARE DISEASES AND ORPHAN PRODUCTS feel isolated and alone as they face the challenges of finding helpful infor- mation, learning a new medical language, and generally charting their way in a daunting new world. As described in Chapter 1, some rare conditions are extremely rare, found in only a few or a few dozen people. Others occur in hundreds, thousands, or as many as 200,000 people in the United States. Many are genetic in origin or have a genetic component. Others arise from exposure to infections or toxins, from faulty immune responses, or occasionally from adverse responses to therapeutic interventions for other conditions. For many rare conditions, the causes are frustratingly elusive. Although people may think of a rare disease as something that hap- pens to someone else, rare diseases can afflict anyone, at any age. They can be acute or chronic. Many are debilitating and present an ongoing risk of death. Some are inevitably fatal given current medical options. Approved therapies are available to treat several hundred of these conditions, but most currently have no therapy that cures or modifies the disease itself. For the rarest conditions, the literature may consist of a single published report describing a few individuals with a previously unidentified genetic syndrome. For other conditions, including a number of the relatively more common conditions such as cystic fibrosis, sickle cell disease, and some can- cers, publicly and privately sponsored research has generated a knowledge base that may encompass epidemiology (including natural history studies), genetics, disease mechanisms, diagnostic tests and standards, biomarkers and outcome measures, effective treatments, and evidence-based guidelines for clinical services. Faced with these realities, many patients and families turn to advocacy groups concerned with specific diseases or to umbrella organizations such as the National Organization for Rare Disorders (NORD) and the Genetic Alliance for support and for information about their condition and avail- able resources. As discussed at the end of this chapter, they may also join together to create new organizations. This chapter begins with a general overview of what is known about the epidemiology of rare diseases based on data and analyses from the United States and Europe. Epidemiologic studies can provide clues and directions for basic and clinical research to determine the causes and mechanisms of rare diseases and develop methods to prevent, diagnose, and treat these conditions. Subsequent sections of this chapter discuss the varied causes of rare diseases and examine in broad terms the range of available preventive, diagnostic, and treatment strategies for diverse rare diseases. The last sec- tion considers the impact of a rare condition on patients, families, and the broader community and recognizes the efforts by patients, families, and advocacy groups to try, in turn, to have an impact on the disease and those affected by it. Reflecting the large number of rare diseases, their great vari-

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 PROFILE OF RARE DISEASES ability, and the scarcity of systematic information about the spectrum of rare diseases collectively, the chapter makes frequent use of examples. EPIDEMIOLOGY OF RARE DISEASES Defining and counting rare diseases is not straightforward. Difficulties in obtaining definitive diagnoses contribute, as do limitations in systems for reporting and tracking such diagnoses. In addition, as described in Chap- ter 1, countries have adopted different definitions of a rare disease, and researchers are continuously identifying new diseases or disease variants. Therefore, the epidemiology of rare diseases—including the determination of prevalence (the number of people affected at any one time), incidence (the number of new cases in a given year), and patterns of disease (e.g., age distribution) in the population—is inexact. Moreover, some conditions that initially are classified as rare eventu- ally outgrow that categorization. For example, when AIDS emerged in the United States, it fit the legislative definition of a rare disease—affecting fewer than 200,000 individuals. As the infection spread, as diagnostic capa- bilities and data collection systems improved, and as researchers developed effective treatments that reduced mortality without curing the disease, the total number of individuals with AIDS grew to nearly 470,000 by 2007 and the number of individuals with HIV infection exceeded 1.1 million (CDC, 2009c).1 If effective but not curative treatment can turn a rare disease into a common one, effective prevention can, conversely, turn a common condi- tion into a rare disease. This is the case with many once common childhood infections such as mumps and measles. Public health officials are concerned, however, that factors such as the development of drug-resistant infectious agents and the opposition of some parents to childhood vaccinations could reverse the situation for some now rare diseases. The former concern—drug resistance—is partly a significant scientific challenge (i.e., developing new anti-infectives) and partly a public health and clinical practice challenge (i.e., discouraging overuse of antibiotics). Preventing negative health con- sequences from anti-vaccination sentiment involves public health expertise, social science research, clinician communication skills, and public policy responses. 1 Under the Orphan Drug Act as described in Chapters 1 and 3, once a drug is designated as an orphan and undergoes further development, it then can be approved and qualify for 7 years of marketing protection even if the prevalence of the disease or condition at the time of approval exceeds the rare disease threshold.

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 RARE DISEASES AND ORPHAN PRODUCTS Objectives, Types, and Uses of Epidemiologic Studies of Rare Diseases The objectives of epidemiologic research in rare diseases include deter- mining the extent, distribution, and burden of these diseases at the popula- tion level and helping identify factors that may cause or contribute to their development. Basic epidemiologic studies generate estimates of incidence and prevalence. For congenital disorders, the statistic often reported is the proportion of births (e.g., 1 in 5,000) affected by the condition. Esti- mates may include breakdowns by age, gender, race or ethnicity, place of residence, and other factors that may offer clues to causation for further investigation. Epidemiologic data have a variety of policy uses, including providing the prevalence data to support an “orphan” designation for an investiga- tional or already approved drug. Companies seeking this designation must provide the Food and Drug Administration (FDA) with documentation that the proposed indication or use for the drug involves fewer than 200,000 people in the United States.2 For manufacturers seeking a Humanitarian Device Exemption, the FDA must document that the device is intended to treat or diagnose a disease or condition that affects fewer than 4,000 people in the United States per year. Policy makers may also consider epidemiologic information on preva- lence and disease burden—in combination with scientific, political, eco- nomic, ethical, and other factors—in making decisions about the allocation of resources for biomedical research. Decisions about research spending, for example, sometimes favor the relatively more common rare conditions such as ovarian cancer, neurofibromatosis, and sickle cell disease, but decision makers also have directed resources to extremely rare diseases, consistent with the value judgments underlying the adoption of special policies to encourage research on rare diseases. (See the analysis of National Institutes of Health [NIH] funding in Chapter 4.) Natural history studies are another pillar of epidemiologic research on rare conditions. These studies track the course of a disease over time, identifying demographic, genetic, environmental, and other variables that correlate with its development and outcomes in the absence of treatment. Natural history studies have also generated important information about clinical (phenotypic) variation and have helped to identify subtypes of rare disorders that may be produced by different genes or by epigenetic factors that influence the effects of a gene. Such longitudinal studies are often a high priority for a rare disease organization or others interested in a poorly 2 Rarely, as discussed in Chapter 3, a sponsor will ask for designation based on another option provided by the Orphan Drug Act: that a condition affects more than 200,000 in the United States but there is no reasonable expectation that the cost of developing a drug for that condition will be recovered from sales in the United States.

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 PROFILE OF RARE DISEASES understood condition. Longitudinal studies of various sorts may also illu- minate treatment effects. Although natural history studies are not the primary focus of govern- ment- or industry-funded research, NIH and pharmaceutical companies as well as other entities do sponsor natural history studies of varying scope and complexity.3 For example, members of the NIH Rare Diseases Clinical Research Network (see Chapter 5 and Appendix E) are undertaking such studies for a number of rare conditions, including several neurological dis- orders and several forms of vasculitis. Understanding the natural history of a disease is an important step in the development of therapies. As discussed in Chapter 3, FDA staff have identified the lack of such studies as a problem with some applications for approval of orphan drugs. In 2008, participants in a workshop sponsored by the National Heart, Lung, and Blood Institute and the Office of Rare Diseases Research at the NIH discussed models for analyzing genotype-phenotype associations in rare diseases and made recommendations for more longitudinal studies and also for refinements in study protocols and better tools to evaluate the resulting data (NHLBI, 2008a). It is too early to judge whether these recommendations will yield more high-quality proposals, an improved infrastructure, and more funding for such studies, which are challenging even for common conditions. Recommendations in Chapters 4 and 5 ad- dress problems with tissue banking practices and arrangements that limit or complicate their use for natural history and other studies. Many epidemiologic data for rare diseases come from studies of single diseases. These studies are sponsored by a multitude of different sources and employ a range of methods and data. Data for prevalence or incidence calcula- tions may come from birth certificates or death certificates; hospital discharge, insurance claims, and other administrative databases; patient registries; special surveillance studies; and newborn and other screening programs. National data collection programs tend to focus on more common conditions, but information about the prevalence and incidence of some 3 For example, a search of the database ClinicalTrials.gov yielded 50 studies using the search term “natural history study” and 1,613 studies using the term “natural history.” Among the NIH-supported natural history studies that involved rare conditions were studies of sickle cell disease (NCT00081523), neurofibromatosis type I (NCT00924196), hereditary hemorrhagic telangiectasia (NCT00004649), Rett syndrome (NCT00299312), stiff person syndrome (NCT00030940), Smith-Magenis syndrome (NCT00013559), and acromegaly (NCT00001981). The last cited study began in 1985 and continues. Examples of pharmaceu- tical company-funded studies include metachromatic leukodystrophy (NCT00639132, Shire); mucopolysaccharidosis I (NCT00144794, Genzyme); and infantile globoid cell leukodystro- phy (NCT00983879, Zymenex A/S). (The numbers in parentheses are identifiers used for the ClinicalTrials.gov database, which was developed by NIH and FDA.)

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 RARE DISEASES AND ORPHAN PRODUCTS rare conditions is generated through systematic disease tracking systems.4 The Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute (NCI) collects data on a number of cancers, including some that are relatively uncommon. At the Centers for Disease Control and Prevention (CDC), programs on infectious diseases and birth defects track and report data on several rare conditions. The Agency for Toxic Substances and Disease Registry (ATSDR) tracks data on exposures to toxic substances with a focus on hazardous waste sites. The American Association of Poison Control Centers aggregates surveillance data from regional poison control centers, which report information on a broad range of poisonings, including those resulting from prescription and over-the- counter drugs, household products, and insect bites. As newborn screening programs become more consistent in the United States, they may provide firmer data on the birth incidence of a number of genetic conditions. Work is continuing to develop a standard framework for reporting the results of newborn screening tests as part of electronic health records and also for analysis of trends by public health agencies (see description at http://newbornscreeningcodes.nlm.nih.gov). For many rare conditions, one difficulty confronting epidemiologic studies involves the lack of condition-specific codes in the World Health Organization’s (WHO) International Classification of Diseases (ICD). The ICD provides the international standard diagnostic classification that is used for epidemiologic studies as well as for key health system management functions. To cite an example of the problem with lack of specific codes, a single ICD code (E75.2) covers Fabry disease, Gaucher disease, Krabbe disease, Niemann-Pick disease, Farber’s syndrome, metachromatic leuko- dystrophy, and sulfatase deficiency. (Codes for endocrine, nutritional, and metabolic diseases can be viewed at http://thcc.or.th/ICD-10TM/ge70.htm.) At the urging of a European rare diseases task force, WHO has created an advisory group to make recommendations about coding improvements for rare diseases. That group has been circulating draft materials for comment, which will be followed by field testing; implementation of coding changes is not expected until after 2015 (Aymé, 2009; Tejada, 2009). This project is complex, but its recommendations, if implemented, should strengthen the foundation for epidemiologic and other research on rare diseases. Much of the preparatory work on rare disease coding has been conducted by Or- phanet, a European information consortium (originally established by the French Ministry of Health) (Aymé, 2009). Orphanet is also the source of the prevalence data discussed below. 4 International efforts are also important. For example, the International Network of Pae- diatric Surveillance Units, which does not include the United States, has supported studies that have described the molecular epidemiology and genotype-phenotype correlations for Rett syndrome, Prader-Willi syndrome, and Smith-Lemli-Opitz syndrome (Grenier et al., 2007).

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 PROFILE OF RARE DISEASES Prevalence Data on Rare Diseases It is estimated that FOP [Fibrodysplasia Ossificans Progressiva] affects about ,00 people worldwide, or approximately one in two million people. Such statistics may be better grasped by the following example: if a large football stadium holds 00,000 fans, one would need to fill nearly 0 football stadiums to find one person who has FOP. At the present time, researchers are aware of approximately 00 people throughout the world who have FOP. IFOPA, 2009, p. 3 “Who else has this rare disease? How many of us are there? What can I expect now? What is known or not known about this disease?” These are among the questions that patients and family members ask as they become, out of necessity, advocates for themselves or others. One step in learning about a rare disease is to determine its prevalence. The prevalence of a disease in an area or jurisdiction may be expressed as the number, percentage, or proportion of people alive on a certain day who have been diagnosed with the disease. As described in Chapter 1, the European Union defines a rare disease as one with a prevalence of no more than 50 people per 100,000 population, whereas the United States sets a numerical maximum of fewer than 200,000 people in this country. Prevalence is a function of both the incidence of disease (number of new cases reported in a given period) and the survival (duration of ill- ness for self-limiting or curable diseases such as many infections). Table 2-1 displays NCI data that highlight how differences in survival affect the prevalence of three types of cancers with similar incidence rates but very different survival rates: poor for pancreatic cancer, intermediate for leuke- TABLE 2-1 Differences in Prevalence for Three Cancers with Similar Numbers of New Cases per Year but Different Survival Rates, 2006 Estimated New Cases Prevalence (complete)a (2009 estimate in parentheses) Thyroid 30,180 (37,200) 410,404 Leukemia (all types) 35,070 (44,790) 231,857 Pancreas 33,730 (42,470) 31,180 (invasive) aAs defined by SEER, complete prevalence represents the number or proportion of people alive on a certain day who have been diagnosed with a disease, regardless of when the condition was diagnosed. SOURCES: Incidence: http://seer.cancer.gov/csr/1975_2003/results_single/sect_01_table.01. pdf; http://seer.cancer.gov/csr/1975_2006/results_single/sect_01_table.01.pdf. Prevalence: http://seer.cancer.gov/csr/1975_2006/results_merged/topic_prevalence.pdf.

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 RARE DISEASES AND ORPHAN PRODUCTS mia (all types considered together), and good for thyroid cancer.5 Survival for pancreatic cancer is so poor that the estimated number of new cases per year can be higher than the estimated number of people surviving at a given time during the year.6 The committee found no broad compilation of data on the prevalence or incidence of rare diseases in the United States. It did, however, locate a recent report from Orphanet that lists estimated European prevalence for almost 2,000 rare diseases (out of an estimated 5,000 to 8,000 such condi- tions) (Orphanet, 2009). The list has much in common with the NIH list of rare conditions cited in Chapter 1. The demography, living conditions, and other characteristics of Europe and the United States likewise have much in common. Thus, despite the limitations discussed below, the committee believes that the overall portrait of rare diseases prevalence in the Orphanet report is likely to approximate that in this country. Figures 2-1A-D show the distribution of rare conditions according to prevalence as presented in the Orphanet report. They reveal an overall distribution that is highly skewed to very rare conditions. In fact, data for approximately 1,400 of the approximately 2,000 conditions (about 70 percent) consist only of case reports for individuals or families. For the conditions not included in the study, the distribution may be even more skewed given that the project began with what were thought to be the more common rare conditions (Eurodis, 2005). In general, the limitations of the data in the Orphanet report include the use of single numbers for conditions with widely varying estimates of prevalence in the literature7 and the lack of bibliographic citations and explanatory details.8 The committee did not systematically check the data presented in the report, but it did note that a few of the listed conditions 5 SEER identifies four primary types of leukemia: acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML) but also reports data on several other types (Horner and Ries, 2007). 6 An NCI working group has defined rare cancers as having an incidence of 40,000 or fewer cases rather than in terms of prevalence (Mikhail, 2005). This specification apparently relates to the specific challenges of clinical research involving populations that include many individuals who have undergone therapies, sometimes multiple therapies. 7 For example, the prevalence report lists malignant hyperthermia (a rare, life-threatening reaction to certain anesthetics and other agents) with an estimated prevalence of 33 per 100,000 population, but a 2007 study published in the Orphanet journal cites a highly vari- able incidence from 1/5,000 to 1/50,000–100,000 anesthesia episodes (Rosenberg et al., 2007). For Prader-Willi syndrome, the prevalence report cites a figure of 10.7/100,000, whereas an article in an Orphanet-associated journal cited a range of 1/15,000 to 1/30,000 (Cassidy and Driscoll, 2009). 8 The report does not include citations of source data but generally cites EMEA (European Medicines Agency), new scientific publications, gray literature, and expert opinion (Orphanet, 2009). Short overview discussions of individual conditions in the Orphanet database vary in the specificity of their citations of sources.

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 PROFILE OF RARE DISEASES 500 450 Number of diseases 400 300 200 71 100 30 21 13 0 0.1-10.0 10.1-20.0 20.1-30.0 30.1-40.0 40.1-50.0 Prevalence per 100,000 FIGURE 2-1A Number of rare diseases by prevalence up to 50/100,000. Figure 2-1A 250 198 Number of diseases 200 150 100 59 38 33 33 50 23 22 18 15 11 0 <0.1 1.1- 2.1- 3.1- 4.1- 5.1- 6.1- 7.1- 8.1- 9.1- -1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 9.0 10.0 Prevalence per 100,000 FIGURE 2-1B Number of rare diseases by prevalence of 10/100,000 or less. (e.g., autism, pulmonary fibrosis) are not rare in the United States. The introduction to the report explicity notes (Orphanet, 2009, p. 2) Figure 2-1B a low level of consistency between studies, a poor documentation of meth- ods used, confusion between incidence and prevalence, and/or confusion between incidence at birth and life-long incidence. The validity of the pub- lished studies is taken for granted and not assessed. It is likely that there

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0 RARE DISEASES AND ORPHAN PRODUCTS 450 400 360 Number of diseases 350 300 257 221 250 174 200 130 150 86 100 50 8 5 0 1-4 5-9 10-24 25-49 50-99 100- 500- 1000- 499 999 5000 Number of published cases (individual) FIGURE 2-1C Number of rare diseases by number of individual cases in literature. 65 70 60 Number of diseases 50 42 Figure 2-1C 35 40 30 15 15 20 10 0 1 2-4 5-9 10-19 20-400 Number of published cases (families) FIGURE 2-1D Number of rare diseases by number of family cases in literature. SOURCE: Orphanet, 2009. is an overestimation for most diseases as the few published prevalence surveys are usually done in regions of higher prevalence and are usually based on hospital data. Therefore, these estimates are an indication of the assumed prevalence but may not be accurate. Figure 2-1D The factors cited illustrate problems inherent in trying to develop reli- able prevalence estimates for rare conditions—individually and collectively. Again, notwithstanding these limitations, the committee expects that the

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 PROFILE OF RARE DISEASES data provide a rough approximation of the overall distribution of rare conditions, at least for the conditions included. In part because data on many conditions are limited to case reports or special population studies, no well-supported estimate exists for the number of people collectively affected by rare diseases. A 1989 government report stated that 10 million to 20 million Americans had a rare condition (NCOD, 1989); the corresponding estimates in 2009 range from 25 million to 30 million (see, e.g., ORDR, 2009). The estimates were not accompanied by analyses or substantive citation of sources. CAUSES OF RARE DISEASES “How did this happen? Why did this happen to me? What can I do?” Individuals and families struggle with these questions as they try their best to grasp the meaning and impact of a rare disease diagnosis. In the past two decades, epidemiologic, molecular, and other research that takes advantage of scientific and technological advances in the biological sciences has greatly increased the number of rare diseases that have an identified cause—usually, although not invariably, genetic. The Orphan Drug Act, the Rare Diseases Act, and other policy initiatives discussed in this report have contributed to this knowledge by focusing attention, resources, and incentives on the study of rare conditions and products to treat them. Knowing the genetic, infectious, or other cause of a disease does not necessarily mean that researchers understand the mechanism of the dis- ease. For example, much remains to be learned about Von Hippel-Lindau syndrome, even though mutations in the VHL gene have been identified as the cause and another gene has been implicated in phenotypic variations (Woodward and Maher, 2006). Moreover, a number of more common rare diseases such as cystic fibrosis and sickle cell disease have known causes and reasonably well understood mechanisms but lack cures, satisfactory treatments, or preventive strategies. Nonetheless, identifying the cause of a condition is usually an important step in building the knowledge base for prevention or effective treatment. Some rare conditions have multiple possible types of causes. For ex- ample, some forms of aplastic anemia, which is caused by damage to stem cells in the bone marrow and is diagnosed in about 500 to 1,000 people each year in the United States, are inherited (e.g., Fanconi anemia). More often, though, the condition is acquired as a result of a toxic exposure (e.g., benzene, chloramphenicol), an infection (e.g., hepatitis, herpes virus), radiation or chemotherapy, or another disease (e.g., rheumatoid arthritis) (NHLBI, 2009). Doctors sometimes cannot determine the cause for a spe- cific patient.

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 RARE DISEASES AND ORPHAN PRODUCTS response to treatment has progressively decreased; from 31 in 1983, to 20 in 1993, to 17 in 2008” (Campeau et al., 2008, p. 11). It also reported that the number of conditions that fully responded to treatment increased from 8 in 1983 and 1993 to 20 in 2008. As reasons for this progress, the authors cited “new small molecules, new enzyme replacement therapies, more conditions that can be treated by organ and cell transplantation, and new experimental approaches” (p. 11). These analyses involve small and highly selected subsets of all genetic diseases and are likely biased toward those that are well studied and for which there are treatments. A 2004 textbook review of treatment for genetic diseases observed that treatments judged to be successful initially may later show their limi- tations (Nussbaum et al., 2004). This pattern may reflect the recognition over time of subtler manifestations of the disease, long-term adverse effects of treatment, and manifestations of the disease not recognized until treat- ments allowed longer survival. Because drugs are approved on the basis of relatively short-term clinical data involving unrepresentative patient popu- lations, FDA often requires drug sponsors to undertake additional studies following the approval of a drug for marketing. The 2004 review linked the “unsatisfactory” state of treatment for genetic conditions to lack of identi- fication of the causal gene; inadequate understanding of pathophysiology; and irreversible damage at the fetal stage before diagnosis. Dietz (2010) recently reviewed therapeutic approaches to Mendelian disorders, focusing on approaches that use detailed knowledge of disease pathogenesis. This review, which is cited further in Chapter 4, explores how such understanding is contributing to investigations involving, for example, the replacement of deficient gene products (gene therapy, enzyme replacement therapy); the use of FDA-approved drugs in novel ways; the design of new small-molecule compounds; and the manipulation of gene expression. To repeat a theme of this report, research resources for rare diseases are limited, both collectively and individually. Nonetheless, basic and clinical research have yielded disease-modifying therapies for many conditions. Table 2-2 illustrates the range of treatments—from surgery to diet and from stem cell therapy to environmental adaptation—that may be de- ployed for specific rare conditions. Some of these therapies have been used for decades, while others have emerged through technological advances. Many of the procedures cited are accompanied by complex pharmaceutical regimens—some short-term, others indefinite (e.g., use of immunosuppres- sive drugs following an organ transplant). As with any therapy, expected benefits are often accompanied by risks that may include significant harms. It is important for patients and families to understand and weigh both po- tential benefits and potential harms of treatment options. Another way of looking at treatments for rare diseases is to consider

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 PROFILE OF RARE DISEASES TABLE 2-2 Examples of Currently Available Treatments or Treatments in Development for Rare Diseases Therapeutic Category Treatment Example Rare Condition Small-molecule compounds Imatinib Chronic myelogenous leukemia Protein therapies Enzyme replacement therapy Gaucher disease Metabolic therapies Sodium phenylbutyrate Urea cycle disorders Nutritional therapies Phenylalanine-restricted diet Phenylketonuria Environmental modification Avoidance of sunlight Xeroderma pigmentosa or adaptation Medical procedures Phlebotomy Hemochromatosis Surgical procedures Open heart surgery Tetralogy of Fallot Medical devices Orthopedic implant Thoracic insufficiency (e.g., Jeune syndrome) Organ transplants Combined liver-kidney transplant Primary hyperoxaluria Bone marrow or cord Bone marrow or cord blood Hurler syndrome blood transplants transplant Stem cell transplants Neural stem cell transplant Neuronal ceroid (investigational) lipofuscinosis Genetic therapies Exon skipping Duchenne muscular (investigational) dystrophy SOURCE: This table draws from Nussbaum et al., 2004; Dietz, 2010; Maegawa and Steiner, in press. the range of effectiveness of treatments or the variability in what is antici- pated from the use of different therapies. Treatments may be • curative, • disease modifying, or • symptom or function modifying. Curative Treatments Truly curative treatments for rare conditions are themselves rare. Im- mediate treatment may be completely successful for all or most cases of cer- tain rare infections (e.g., Tropheryma whipplei) or certain rare poisonings (e.g., from snakebites or cyanide). Vitamin D supplementation generally cures rickets, although for one form (X-linked hypophosphatemic rickets), a combination of phosphate and a form of vitamin D will treat but not cure the condition (Imel et al., 2010). Some rare anatomical defects can be corrected (essentially cured) with

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 RARE DISEASES AND ORPHAN PRODUCTS surgery, for example, coarctation of the aorta. Certain conditions that can be treated effectively with surgery, such as transposition of the great arter- ies or tetralogy of Fallot, have features beyond the intrinsic anatomical anomaly that require continued medical attention. Organ transplantation is considered curative for a few rare conditions, for example, heart transplantation for hypoplastic left heart syndrome. For carefully selected subsets of patients, bone marrow transplantation or transplantation of stem cells from umbilical cord blood is, if success- fully performed, considered a cure for Diamond-Blackfan anemia, Wiskott- Aldrich syndrome, and paroxysmal nocturnal hemoglobinuria as well as as some cancers (Filopovich et al., 2007; Brodsky, 2009; Clinton and Gazda, 2009). Although they may be considered cures, such procedures come ). . with significant short- and long-term health risks from the procedure itself and the necessary follow-up care (e.g., use of immunosuppressive drugs). Moreover, transplants are sometimes lifesaving but not curative. For ex- ample, umbilical stem cell transplant can save some children with infantile Krabbe disease from death, but they will still have major neurologic deficits (Duffner et al., 2009). Disease-Modifying Treatment Disease-modifying therapies are targeted to the underlying pathology of a disease in order to prevent its progression or otherwise limit the harm it creates. For example, with galactosemia, a potentially fatal disorder of galactose metabolism, the restriction of milk products immediately upon diagnosis through newborn screening will interfere with the pathology of the disease and prevent its severe manifestations. Children may still, how- ever, experience various problems such as speech and language difficulties (Lai et al., 2008). Kidney transplantation is lifesaving but not curative for individuals who have nephropathic cystinosis; early initiation of disease- modifying treatment with cysteamine can significantly delay complications (Kleta and Gahl, 2004) For many disease-modifying therapies, the treatment effect is short- lived and must be repeated indefinitely. Examples include enzyme replace- ment therapies for conditions such as Gaucher disease, which involves the ongoing use of a biologically created product to act in place of the enzyme that is missing or deficient as a result of a genetic defect. Depending on the condition, such therapy may be effective for some manifestations of the disease but not others (e.g., liver- and bone-related but not brain-related aspects of Gaucher disease) (Schmitz et al., 2007). In some cases, the mechanism of action of a disease-modifying drug may not be clear. An example is riluzole, which is associated with a modest survival benefit for amyotrophic lateral sclerosis (Bellingham, 2010). An-

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 PROFILE OF RARE DISEASES other example is hydroxyurea, which is the only disease-modifying therapy identified for sickle cell disease (Segal et al., 2008). Rational drug design specifically aims to develop new drugs based on knowledge of disease biology. This strategy holds promise for many rare conditions for which no disease-modifying therapies are known. Current treatment for these conditions still emphasizes treatment of symptoms and prevention of complications. Symptomatic and Functional Therapies Symptomatic treatments are vital to patient well-being for many chronic rare conditions, especially when more definitive therapies are not available. Painful and distressing symptoms of many rare as well as common diseases include pain, nausea, bladder or bowel dysfunction, itching, dizziness, movement limitations, and speech dysfunction to name a few. Treatments also seek to treat or prevent other disease- or treatment-related complica- tions, for example, infections (such as the bronchitis or pneumonia caused by cystic fibrosis or primary ciliary dyskinesia), anemia (such as that as- sociated with hereditary spherocytosis), and delayed growth (such as that associated with X-linked hypophosphatemic rickets). To temper symptoms and preserve or improve physical, intellectual, and emotional functioning, clinicians may use a wide variety of therapeutic methods. These include medications, nutritional agents, surgical proce- dures, psychotherapy, physical and occupational therapy, complex medi- cal devices (e.g., sophisticated communication devices), and less complex devices (e.g., braces). The above discussion emphasizes the physical dimensions of treatment. Care-giving extends well beyond the physical to include psychological, spiritual, and practical support. These dimensions of care may be especially significant for individuals and families facing serious illness. Genetic coun- seling is important for individuals and families facing the new diagnosis of a genetic disorder. Also, because many rare disorders are fatal, end-of-life care is important to help patients (to the extent they are able to participate) and families plan for an expected but not necessarily predictable death and to make difficult decisions about the site and nature of care. After a death, continued support can help families and others cope with grief and other consequences of loss. Delivering Preventive, Diagnostic, and Treatment Services A variety of factors—including lack of knowledge, lack of resources, or failure to follow recommendations—may interfere with a physician’s or patient’s use of effective diagnostic techniques, preventive measures, and

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 RARE DISEASES AND ORPHAN PRODUCTS treatments. Although this report focuses on research and development and not the movement of effective treatments or preventive or diagnostic mea- sures into practice, that movement is crucial if the benefits of research are to be realized in the lives of patients and their families. One common mission of advocacy organizations is to educate clini- cians about rare conditions as a means of improving the provision of care, including the appropriate consideration of new diagnostic and therapeutic options. Depending on the condition and the organization, other strate- gies may include the development of clinical practice guidelines, quality improvement and assessment programs (including incentives for meeting quality standards), and continuing medical education and consumer educa- tion activities. This section briefly discusses just a few issues in health care delivery that may affect the availability or quality of care provided to people with rare conditions. It does not examine the development and use of clinical practice guidelines, the challenges of emergency care, the role of electronic health records or information systems, or the cost or financing of services. Chapter 6, however, examines health plan coverage and reimbursement of orphan drugs, and Chapter 7 examines coverage and reimbursement of devices marketed for small populations under a Humanitarian Device Exemption. Specialized Centers for Rare Diseases For both common and rare diseases, the creation of medical centers or medical practices specializing in the diagnosis and treatment of a disease is a frequent strategy to improve the quality and consistency of care. For rare diseases, specialized centers can offer consultations to outside clini- cians, develop care guidelines based on available evidence and experience, and serve as an established referral site in emergencies or other situations in which local resources are insufficient. These centers can also provide a base for research. One of the early priorities of the Cystic Fibrosis Foundation (CFF) was the establishment of a network of accredited care centers. From two centers at the outset in 1961, CFF now accredits 115 care centers as well as 95 adult care programs (CFF, 2008, undatedb). The foundation has also designated 10 centers as basic research centers and more than 70 as sites for its Therapeutics Development Network (CFF, undatedb). In 1972, Congress authorized the creation of comprehensive research and treatment centers for sickle cell disease. These centers were subsequently established by what is now the National Heart, Lung, and Blood Institute. In 2007, the American Society of Hematology recommended a number of revisions in the program “to ensure that clinical research is conducted in

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 PROFILE OF RARE DISEASES a milieu where federally funded comprehensive care programs include a much larger proportion of children and adults with sickle cell disease than is currently served by existing centers, networks, and other governmental support programs” (ASH, 2007). In addition, the organization has recom- mended changes in the program to promote multidisciplinary, multicenter, collaborative research and more resources for translational research. Among other examples of specialized centers to improve care delivery, the Children’s Tumor Foundation has created a Neurofibromatosis Clinic Network of affiliated clinics that meet operational principles established by an advisory board. The organization had recognized 38 such clinics in the United States by the end of 2008 (CTF, 2009). The CDC funds compre- hensive treatment centers, including more than 130 for hemophilia, 8 for thrombosis and hemostasis, and 6 for thalassemia (CDC, 2009b). In addition to bringing together comprehensive expertise and resources to address an array of patient needs, specialized care centers make it easier for sponsoring organizations and others to establish and monitor the qual- ity of care and other standards. For rare diseases, however, the evidence base to establish standards may be limited, and the number of patients may be too small for some statistical tracking tools to be very useful. For extremely rare diseases, networks of comprehensive care centers are the exception, although individual medical centers may still be recognized as loci of clinical expertise. Examples include many of the institutions participat- ing in the NIH Rare Diseases Clinical Research Network (see Chapter 5). In addition to a focus on systems of care, a priority for many advocacy organizations has been to help patients and families identify individual phy- sicians with some experience and expertise with extremely rare conditions. Organizations may provide a list of physician contacts, as exemplified by the website of the International Fibrodysplasia Ossificans Progressiva (FOP) Association, which lists physician contacts, including clinical researchers at the FOP Research Laboratory at the University of Pennsylvania (who are also cited as emergency contacts). In addition, as noted earlier, NIH has created the Undiagnosed Diseases Program, which sees patients through the NIH Clinical Center. Pediatric-Adult Care Transition Children form a substantial part of the population with rare conditions. Although many rare diseases are fatal in infancy or childhood, early diagno- sis and improved treatment for a number of conditions have increased the number of infants and children who survive to adulthood. For this group, the transition from pediatric or adolescent to adult care is often a matter of acute concern to the young people themselves, their families, and the profes- sionals who care for them. One review of the importance of managing this

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 RARE DISEASES AND ORPHAN PRODUCTS transition noted that even in situations when the need was long anticipated, for example, for children with phenylketonuria (PKU), the response has still fallen short (Scriver and Lee, 2004). Table 2-3 highlights characteristics of child and adolescent health that may affect the transition from pediatric to adult care for children with seri- ous chronic conditions. To the extent that young people in transition lose health insurance through a parent’s work-based coverage or under Medi- caid, the shift from pediatric to adult care may create additional complica- tions and risks. Medicaid covers a range of special services for children that are not usually covered for adults and that may be particularly important for children with severely debilitating rare conditions. For many serious chronic conditions that begin at birth or in childhood, children’s hospitals usually have a depth of expertise and multidisciplinary inpatient and outpatient care coordination that will not be matched by other medical centers that treat adults (IOM, 2007). Treatment of serious, chronic, rare conditions often involves multiple specialties such as medi- cal genetics, neurology, gastroenterology, psychiatry, endocrinology, and physical therapy. Particularly for conditions that still often result in death in early adulthood, the adult center may have no specialists with experience treating those conditions. Recognizing the complexities of and deficiencies in chronic care co- ordination generally, the American College of Physicians (ACP, 2004) has followed the American Academy of Pediatrics (AAP, 2002) in endorsing the concept of the medical home as a centerpiece for medical care and other coordination. In principle, the implementation of this concept would sup- TABLE 2-3 Characteristics of Child and Adolescent Health That May Affect the Complexity of Health Care Transitions Simpler Transition More Complex Transition Single health condition Multiple health conditions Low risk of future health problems High risk of future health problems No dependence on medical equipment Reliance on life-sustaining medical equipment Rare acute illness, medically stable Frequent acute episodes, medically unstable Few medications Multiple medications, medication problems No cognitive impairments Profound mental retardation No physical impairments Serious physical impairments Mentally healthy Mentally ill No behavioral concerns Serious behavioral concerns SOURCE: IOM, 2007 (adapted from Kelly et al., 2002).

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 PROFILE OF RARE DISEASES port smooth transitions from pediatric to adult care for children with rare conditions. IMPACT OF RARE DISEASES ON PATIENTS, FAMILIES, AND COMMUNITIES I found that families don’t have feelings. . . . Individuals do. My feelings about this were different from my wife’s, and those are different from my daughter’s. Everyone has their own, very individual experience. That has had an important impact on how our family has dealt with all of it. It’s something that all families need to recognize when they are going through a shared experience like this. Just because you feel or react one way, doesn’t mean your wife or children are experiencing the same thing in the same way. It was quite a thing to realize. Hollaway, 2007 Rare diseases take their toll on all involved, from affected individu- als and their families and friends, to the health professionals who care for them, to their communities, and the larger society. Many rare diseases result in premature death of infants and young children or are fatal in early adulthood. Such premature deaths can have lifelong effects on par- ents, siblings, grandparents, and others close to a family. Frequently, rare conditions produce devastating long-term functional, physical, and mental disabilities that strain families’ emotional and economic resources. Even for rare conditions that are less severe, the isolation, the uncertainty about the course of the disease, and the frequent lack of effective treatments can have a significant impact. Just as rare conditions vary, individual and family experiences with debilitating or life-threatening illness clearly vary—as do their responses. The effects of rare conditions on patients and families and their responses are often shaped by socioeconomic status, including differences in income and education. Better outcomes may be linked to medical and nonmedical actions that take such differences in financial and nonfinancial resources into account. Patient and family values also vary. Advocacy groups and educators encourage health care professionals to respect these values as they help patients and families understand what they are facing and make decisions about care and treatment. High and burdensome costs are not unique to rare diseases, but a number of factors can push patient, family, and societal costs higher for rare conditions than for more common ones. The search for an accurate diagnosis can be not only time-consuming but also expensive. Medications developed specifically for rare conditions can be extraordinarily expensive, costing tens or even hundreds of thousands of dollars per year. Many rare

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0 RARE DISEASES AND ORPHAN PRODUCTS conditions are diagnosed in childhood and then affect individuals for de- cades. Many individuals require extensive, long-term supportive care that is not covered by Medicare or private health plans, although Medicaid may cover such services for those who qualify. Even for relatively well-off indi- viduals and families, the expenses associated with life with a rare disease can be a significant burden. For both individuals and family members, the economic impact of rare diseases extends to lost productivity, lost wages, or the inability to find manageable work with flexible leave, health insurance, and other key benefits. Notwithstanding laws against discrimination based on disability or genetic information (notably the Genetic Information Nondiscrimination Act of 2008, P.L. 110-233), employers may fear the consequences of hiring a person with evident health problems and may take health (including the health of an employee’s family members) into account when making hiring or layoff decisions. For small employers, a single health plan member with extraordinary medical costs can lead to unaffordable premiums for the entire group of employees. As described in Chapter 6, if it survives calls for its repeal, the Patient Protection and Affordable Care Act of 2010 (P.L. 111-148) should make access to insurance easier for many people with rare conditions and should limit certain restrictions on coverage, for example, a lifetime cap on benefits. I did not choose this work as my career; the vocation was bestowed on me more than  years ago when my two children were diagnosed with a genetic disease called pseudoxanthoma elasticum. Terry, 2009 The physical, emotional, and financial impact of a rare disease on indi- viduals and families has motivated many of them to try, in turn, to have an impact on the disease and others affected by it. They have joined together to form support and advocacy organizations—some focused on individual conditions, others encompassing a number of related conditions, and yet others such as NORD and the Genetic Alliance acting as umbrella organi- zations and advocates. Although not focused solely on rare conditions, the Genetic Alliance convenes a range of activities to help rare disease and other groups develop, function effectively, and collaborate. NORD likewise pro- vides assistance to rare disease groups, including newly organized groups. Some groups (e.g., the Vasculitis Foundations, which was founded in 1986 as the Wegener’s Granulomatosis Association) have moved from a concentration on a single condition to a focus on a group of related con- ditions, some of which previously had not had an organized voice. Such movement reflects both the biological reality that knowledge about one condition may be more generally relevant and the organizational reality

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 PROFILE OF RARE DISEASES that consolidation can bring operational efficiencies and greater public recognition (see, e.g., Hoffman, 2006). Many advocacy organizations take on multiple roles, including pro- viding information, supporting patients and families in obtaining needed clinical and other services, offering emotional support, educating clini- cians, shaping public policy, and promoting research. Patients, families, and advocacy groups have been a driving force in public policy. Notably, they pressed for the passage of the Orphan Drug Act and the creation of the Office of Rare Diseases Research at NIH. They likewise were active in working for passage of the Genetic Information Nondiscrimination Act and creation of the compassionate allowances program that allows people with a number of rare conditions to qualify quickly for Social Security Disability Insurance (see Chapter 6). Some rare disease groups and their umbrella organizations argue that efforts to influence public policy should take this broad approach rather than focus on funding or other policies aimed at individual rare diseases (see, e.g., Farmer, 2009; Terry, 2010). As is true for organizations associated with common diseases such as breast cancer or cancer generally, rare disease groups often aim to engage and have an impact on the broader community through public awareness and fundraising efforts. Walks, runs, bike races, telethons, celebrity ap- pearances, and other events involve people in highly visible activities that draw attention to rare conditions and the toll they take. In addition, NORD and other groups promote awareness of rare diseases generally, including through activities associated with Rare Diseases Day. Of particular relevance for this report, individuals, families, and advo- cacy groups have also mobilized to promote the study of rare diseases and the development of products to treat these diseases. In some cases, research is the primary focus of advocacy organizations. Although groups may focus mainly on raising money for research and advocating for more public fund- ing for research, some take more active roles. For example, they may work with researchers by organizing group members to participate in clinical studies, provide personal data for natural history studies, contribute tissue samples, and volunteer in other ways (see, e.g., Farmer, 2009; Frohnmayer and Frohnmayer, 2009; Terry, 2009). They also can direct research to issues of most concern to patients and families (Nijsten and Bergstresser, 2010). The Office of Rare Diseases Research at NIH has made involvement of ad- vocacy groups an important feature of the Rare Diseases Clinical Research Network. Organizational strategies and agendas for supporting research vary depending on the state of knowledge, the organization’s financial resources, the concerns of organizational founders, and other factors. As discussed further in Chapters 4 and 5 and Appendix F, some patient organizations have promoted partnerships with industry and public agencies and devised

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 RARE DISEASES AND ORPHAN PRODUCTS new models of “venture philanthropy” to bridge the gulf between basic research findings and approved therapies (see, e.g., IOM, 2008, 2009b; Kelley, 2009; Ashlock, 2010). In sum, rare diseases have a profound impact on patients and families, but patients and families, in turn, have an impact on the world around them when they organize with others to inform their communities, influ- ence public policy, and stimulate research. Sometimes separately but also in concert, rare disease organizations and their umbrella organizations have worked together on a broad agenda that includes funding for research and technological innovations that will identify the mechanisms of rare diseases and translate these findings into studies that ultimately lead to better ways to prevent, diagnose, and treat these diseases. As this report illustrates, the confluence of scientific advances and policy initiatives provides new op- portunities to accelerate this progress.