The development of drug and biological products intended to treat rare diseases (Orphan diseases) is one of the fastest growing areas of clinical research, and also one of the most challenging. This article provides an introduction to two important regulatory considerations for Orphan drugs: Orphan status designations and general considerations for the administration of investigational agents in early phase clinical trials. Incentives available to orphan drug developers under the Orphan Drug Act (ODA) and requirements for obtaining an orphan status designation are discussed. An introductory overview of ethical and statutory considerations for investigational drugs, requirements for initiating investigational new drug applications (INDs), and sources of information and advice from the US Food and Drug Administration (FDA) are also described.

A recent US Food and Drug Administration (FDA) advisory committee meeting highlighted the potential of clinical pharmacology to overcome challenges in orphan drug development.

Facing substantial obstacles to developing new therapies for rare diseases, some sponsors are looking to 'repurpose' drugs already approved for other conditions and use those therapies to treat rare diseases. In an effort to facilitate such repurposing and speed the delivery of new therapies to people who need them, we have established a new resource, the Rare Disease Repurposing Database (RDRD). The advantages of repurposed compounds include their demonstrated efficacy (in some clinical contexts), their observed toxicity profiles and their clearly described manufacturing controls. To create the RDRD, we matched the US Food and Drug Administration (FDA) orphan designation database to FDA drug and biological product approval lists. The RDRD lists 236 products that have received orphan status designation that is, were found to be 'promising' for the treatment of a rare disease and though not yet approved for marketing for that rare disease, they are already approved for marketing to treat some other disease or condition. The RDRD contains three tables: Orphan-designated products with at least one marketing approval for a common disease indication (N = 109); orphan-designated products with at least one marketing approval for a rare disease indication (N = 76); and orphan-designated products with marketing approvals for both common and rare disease indications (N = 51). While the data included in the database is a re-configuration/cross-indexing of information already released by the FDA, it offers sponsors a new tool for finding special opportunities to develop niche therapies for rare disease patients.

Duchenne muscular dystrophy (DMD) is one of the most commonly recognized dystrophinopathies. There are no approved therapeutic options available for this disease but recent discoveries have led to hope that effective therapies might be forthcoming. With funding from patient advocacy groups, private investors, and governmental bodies such as the Food and Drug Administration Office of Orphan Product Development (FDA/OOPD), gene modification and other molecular therapies are being actively investigated. However, since DMD patients are few in number and disease manifestations vary considerably in early and late stages of disease, obtaining the data needed for full evaluation of putative therapies may prove challenging. Should ambulation remain the focus of Phase 2/3 studies or should consideration be given to the primary causes of late‐stage morbidity and mortality, e.g., cardiac and respiratory dysfunction related to reduced or absent dystrophin production? It seems reasonable to argue that clinical trials planned for DMD should consider the entire population. Muscle Nerve, 2010

Interest in developing drugs for rare diseases has increased substantially in recent years. This article from the US Food and Drug Administration highlights the role of regulators in catalysing further progress in this field.

The Orphan Drug Act encourages the development of products for rare diseases and conditions. Many conditions that stand to benefit from stem cell-based products are rare diseases. We address the Orphan Drug Act in relation to the development of stem cell-based products.

OBJECTIVE: The 1983 US Orphan Drug Act established a process through which promising therapies are designated as orphan products and, later, with satisfactory safety and efficacy data, receive marketing approval and fiscal incentives. We examined accomplishments in drug development for inborn errors of metabolism (IEMs). METHODS: Food and Drug Administration data were used to identify orphan product designations and approvals for IEMs, and the trends for the past 26 years were summarized. Individual clinical development times (CDTs) from filing investigational new drug application to marketing approval were determined. RESULTS: We examined 1956 orphan product designations from 1983 through 2008 and found 93 (4.8%) for IEMs. Of those, 24 (25.8%) received marketing approval. This proportion of approval was significantly (P = .036) higher than that for non-IEM orphan products (17%). Among the IEM products, disorders of complex molecules received the most designations and approvals (61 and 11, respectively). Among the subgroups, lysosomal storage diseases received the most designations and approvals (43 and 9, respectively), whereas mitochondrial diseases (other than fatty acid oxidation disorders) received 7 designations with no approvals. We then examined the CDTs for the approved IEM products and found a median of 6.4 years (range: 2.6–25.1 years). Biological products had significantly shorter CDTs than drugs (mean: 4.6 vs 11.0 years; P = .003). CONCLUSION: For 26 years, the Orphan Drug Act has generated new therapies for IEMs. Why some IEMs have motivated successful drug development and others have not remains enigmatic; yet the needs of IEM patients without treatment are a certainty.

The development of drugs for rare diseases — often known as orphan drugs — is attracting increasing interest and investment, catalysed in part by incentives such as those provided by the 1983 US Orphan Drug Act. This article provides the first comprehensive analysis of 25 years of data on the designation and approval of orphan drugs by the US Food and Drug Administration, with the aim of supporting and encouraging future orphan drug development and approval.

Many neurological diseases or conditions are rare disorders. The Orphan Drug Act (ODA) of 1983 was promulgated to promote the development of products for such conditions. In this Opinion piece, we discuss how the ODA has affected neurological diseases, note how current and future sponsors (any person(s) or entity (i.e., academic, corporate body, individual, manufacturer) that applies for an official regulatory action) of products for rare neurological diseases can take advantage of ODA incentives, identify areas of success and continuing needs, and review data that can help drive the future development of products for rare neurological conditions.

The objective of this study was to use recently available data to describe the epidemiology of melanomas of the esophagus and the anorectum in contrast to melanoma of the skin. The methods used include descriptive epidemiology using cases reported to the Surveillance Epidemiology and End Results registry, 1973-2003. All rates were age adjusted. We found 46 759 cutaneous melanomas, 170 anorectal melanomas and 20 esophageal melanomas, corresponding to age-adjusted rates of 70.1, 0.27, and 0.03 per million population, respectively. Median age of patients with melanoma of the skin was less than those with melanoma of the anorectum or esophagus (55 years vs. 71 years and 69 years, respectively). Rates of melanoma of the skin were 1.5-fold higher for men than for women (87.1 vs. 58.1 per 10); in contrast, rates of anorectal melanoma were 1.6-fold higher for women than for men (0.324 vs. 0.199 per 10). Rates of cutaneous melanoma for whites were 13-fold higher than for blacks (80.6 vs. 6.1 per 10, P<0.001), whereas the rates of anorectal melanoma were 1.7-fold higher among whites than blacks (0.273 vs. 0.173 per 10). Comparing the period 1973-1987 with 1988-2003, the rate of cutaneous melanoma increased 1.4-fold (56.0-80.1 per 10), whereas the rate of anorectal melanoma similarly increased 1.8-fold (0.182 to 0.329 per 10).In conclusion, anorectal melanomas, and especially, esophageal melanomas remain rare malignancies. This is the first report where temporal trends in anorectal melanoma are following the increased incidence of cutaneous melanomas, but it is unclear whether immunohistochemical diagnostic practices have influenced this trend. As gastrointestinal melanomas represent melanocytic transformation in the absence of sunlight, their epidemiology may provide etiologic clues to alternative or systemic transformative factors also operant in cutaneous melanoma.

Background: Carticel is an autologous cultured chondrocyte product that has been approved by the United States Food and Drug Administration for the repair of symptomatic cartilaginous defects of the femoral condyle that are caused by acute or repetitive trauma in patients who have been previously managed with arthroscopy or other surgical procedures. The present report describes the adverse events following Carticel implantation as reported to the Food and Drug Administration from 1996 to 2003. Methods: We reviewed adverse event reports that had been submitted to the Food and Drug Administration's MedWatch system for information on demographic characteristics, adverse events, and surgical revisions. Adverse events were categorized into sixteen non-mutually exclusive groups. Five categories were used to classify reoperations. Food and Drug Administration regulations require manufacturers to report adverse events; however, reporting by clinicians and others is voluntary. Therefore, adverse event reporting is likely to underestimate the number of event occurrences. Adverse events may be either causally or coincidentally related to the product. Results: A total of 497 adverse events among 294 patients receiving Carticel were reported. The median interval from Carticel implantation to the diagnosis of an adverse event was 240 days (range, one to 2105 days). The median age of the patients was thirty-eight years, and 63% of the patients were male. Of the 270 events for which the anatomic site was noted, 258 (96%) involved the femoral condyles. More than one adverse event was reported for 135 patients (46%). The most commonly reported events were graft failure (seventy-three patients; 25%), delamination (sixty-five patients; 22%), and tissue hypertrophy (fifty-two patients; 18%). In addition, eighteen surgical site infections were reported, including eleven joint and seven soft-tissue infections. Surgical revision subsequent to Carticel implantation was mentioned in the records for 273 patients (93%). The reasons for the 389 revision procedures included graft-related problems (187 procedures; 48.1%), periarticular soft-tissue problems (ninety-seven procedures; 24.9%), and intra-articular problems (sixty-three procedures; 16.2%). Eight patients had a total knee replacement. Based on the manufacturer's reported distribution of 7500 Carticel lots between 1995 and 2002, 285 patients (3.8%) had an adverse event that was reported to the Food and Drug Administration. Conclusions: The most common adverse events reported in association with the Carticel technique involved graft failure, delamination, and tissue hypertrophy. Level of Evidence: Therapeutic Level IV. See Instructions to Authors for a complete description of levels of evidence.

Population-based cancer registries, such as those included in the Surveillance, Epidemiology, and End-Results (SEER) Program, offer tremendous research potential beyond traditional surveillance activities. We describe the expansion of SEER registries to gather formalin-fixed, paraffin-embedded tissue from cancer patients on a population basis. Population-based tissue banks have the advantage of providing an unbiased sampling frame for evaluating the public health impact of genes or protein targets that may be used for therapeutic or diagnostic purposes in defined communities. Such repositories provide a unique resource for testing new molecular classification schemes for cancer, validating new biologic markers of malignancy, prognosis and progression, assessing therapeutic targets, and measuring allele frequencies of cancer-associated genetic polymorphisms or germline mutations in representative samples. The assembly of tissue microarrays will allow for the use of rapid, large-scale protein-expression profiling of tumor samples while limiting depletion of this valuable resource. Access to biologic specimens through SEER registries will provide researchers with demographic, clinical, and risk factor information on cancer patients with assured data quality and completeness. Clinical outcome data, such as disease-free survival, can be correlated with previously validated prognostic markers. Furthermore, the anonymity of the study subject can be protected through rigorous standards of confidentiality. SEER-based tissue resources represent a step forward in true, population-based tissue repositories of tumors from US patients and may serve as a foundation for molecular epidemiology studies of cancer in this country.

Objective. To determine the association of race with incidence, histology, treatment, and survival in women with uterine sarcoma during the period 1989-1999.Method. Uterine sarcomas were defined as leiomyosarcoma, carcinosarcoma, high-grade endometrial stromal sarcoma (HGESS), adenosarcoma, and sarcoma not otherwise specified (NOS). We used cases from Surveillance, Epidemiology, and End Results (SEER) program to compare uterine sarcoma among women >35 years of age. Using data from 1989 to 1999, we compared race-specific age-adjusted incidences, histological distributions, extent of disease at diagnosis, and race-specific survival.Results. During the period of 1989-1999, 2677 women were diagnosed with uterine sarcoma, 2098 (78%) of whom were white and 420 (16%) of whom were black, and 159 (6%) of whom were of other races. The overall age-adjusted incidence for blacks was twice that of whites and more than twice that of women of other races (7/10(5) vs. 3.6/10(5) vs. 2.7/10(5), p < 0.0001). Racial differences in the incidence of uterine sarcoma existed for leiomyosarcoma (1.51/10(5) for blacks vs. 0.91/10(5) for whites, and 0.89 for women of other races, P < 0.01) and carcinosarcoma (4.3/10(5) for blacks, vs. 1.7/10(5) for whites, and 0.99 for women of other races, P < 0.001), but not for other histological types. Blacks with stage II disease were less likely to receive radiation in addition to surgery compared to whites (33% vs. 54%, P < 0.05). Five-year relative survival of patients with disease beyond the uterus was significantly longer for those that received radiation and surgery compared to those that received surgery alone. There were no racial differences in survival for women that received similar therapy.Conclusions. Adjuvant therapy improved survival for women with stage II-IV disease. Survival of black and white patients who received comparable treatment was similar. (C) 2004 Elsevier Inc. All rights reserved.

BACKGROUND. Serous and mucinous ovarian tumors of low malignant potential (LMP-S and LMP-M, respectively) are noninvasive tumors that portend excellent survival when confined to the ovary. Comparison of the survival for women with LMP tumors staged as distant with women who have carcinoma may have important implications for diagnostic terminology and clinical management.METHODS. The authors compared relative survival rates among patients diagnosed with ovarian tumors during the period 1988-1999 (with follow-up through 2000) by histologic type, disease stage, tumor grade (for carcinomas), and patient age, using data from the Surveillance, Epidemiology, and End Results Program.RESULTS. The overall relative survival rate at 10 years (+/- 1.96 standard errors) was 96.9% +/- 2.3% for women with LMP-S tumors, 30.4% +/- 1.7% for women with serous carcinoma (CA-S); 94.0% +/- 3.1% for women with LMP-M tumors, and 64.7% +/- 3.4% for women with mucinous carcinoma (CA-M). The survival rate at 10 years for women with distant-stage LMP-S tumors was 89.9% +/- 5.3%, compared with 96.1% +/- 8.6% for women with well differentiated, localized CA-S. The survival rate for women with distant-stage LMP-M tumors at 5 years was 85.5% +/- 9.0%, compared with 95.5% +/- 3.4% for women with well differentiated, localized CA-M (data for 10 years were limited). Mucinous ovarian neoplasms were associated with all excess of second malignancies of the digestive tract.CONCLUSIONS. Relative survival among women with distant-stage LMP tumors was not 100% and resembled the survival of women who had carcinoma exhibiting favorable prognostic features (localized stage). Future studies of women with high-stage LMP tumors are required to clarify the pathogenesis of extraovarian lesions and their implications for management and prognosis. Published 2004 by the American Cancer Society.*

Supported in part by the Centers for Disease Control and Prevention under cooperative agreement U75/CCU515998 to the North American Association of Central Cancer Registries.The authors appreciate the in-kind support from all the contributors to this supplement. The authors are also grateful for the contributions of David Roney and Andrew Lake of Information Management Services (IMS), Inc. for the computer support required for the preparation of analytic files and to the National Cancer Institute for providing support for these computer services.Address for reprints: Holly L. Howe, Ph.D., North American Association of Central Cancer Registries, 2121 White Oaks Dr., Springfield, IL 62704; Fax: (217) 698-0188; E-mail: hhowe@naaccr.org.Received March 18, 2002; revision received September 25, 2002; accepted January 15, 2003.*This article is a US Government work and, as such, is in the public domain of the United States of America.