Orphan Drug Act Research Articles

Insider insight on the orphan drug act

Insider insight on the orphan drug act

Direct-to-Consumer Genetic Testing and Orphan Drug Development.

Since the introduction of the Orphan Drug Act (ODA) in 1983, orphan drug approvals in the United States have jumped from <100 per decade to over 200 per year. This growth is widely attributed to the financial incentives the ODA gives to companies that develop these medicines, and it is likely to continue for a unique reason: partnerships between pharmaceutical firms and direct-to-consumer (DTC) genetic testing companies. This emerging trend is the subject of this article, which begins by considering how rare-disease drugs are regulated and the rising interest in nonclinical genetic testing. It then outlines how DTC companies analyze DNA and how their techniques benefit researchers and drug developers. Then, after an overview of the current partnerships between DTCs and drug developers, it examines concerns about privacy and cost brought up by these partnerships. The article concludes by contrasting the enormous positive potential of DTC-pharma relationships and their concomitant dangers, especially to consumer privacy and cost to the healthcare system.

Ethical imperatives of timely access to orphan drugs: is possible to reconcile economic incentives and patients\u2019 health needs?

BackgroundMore than 6,800 rare diseases and conditions have been identified in the US, which affect 25–30 million Americans. In 1983, the US Congress enacted the Orphan Drug Act (ODA) to encourage the development and marketing of drugs to treat rare diseases and conditions. This study analyzed all orphan designations and FDA approvals since 1983 through 2015, discussed the effectiveness of incentives for the development of treatments for rare diseases, and reflected on the ethical imperatives for timely access to orphan drugs.MethodsStudy data were derived from the Food and Drug Administration (FDA) Orange Book and the Office of Orphan Drugs Development. A search was conducted to assess literature on the ethical principles and economic incentives for the development of orphan drugs.ResultsIn the period 1983–2015, the FDA granted 3,647 orphan drug designations and 554 orphan drug approvals. The orphan drug approvals corresponded to 438 different brand names. Cancer was the therapeutic area with the highest number of approvals. The increased number of patients with rare diseases and the growth in the cost of orphan drugs pose a significant economic burden for patients, public programs and private third party payers. Regulatory differences to qualify for orphan designation and various population thresholds employed by the FDA and the European Medicines Agency lead to further unmet health needs for patients with rare diseases and aggravate health inequities. There is no societal consensus on the population and economic thresholds, the drug effectiveness indicator(s), or the societal value to be placed for the approval and reimbursement of orphan drugs.ConclusionOrphan drug development and marketing in the US concentrate in few therapeutic areas. Despite the increase in the number of FDA approved orphan drugs, the unmet needs of patients with rare diseases evidence that the current incentives are not efficiently stimulating orphan drug development. There is need to balance economic incentives to stimulate the development and marketing of orphan drugs without jeopardizing patients’ access to treatment. Thus, aligning pharmaceutical companies’ incentives with societal budgetary constraints is necessary and the ethical imperatives of timely access to orphan drugs need to be agreed upon.

Incentivizing Orphan Product Development: United States Food and Drug Administration Orphan Incentive Programs.

Over 30years ago, the United States (US) Congress passed the Orphan Drug Act (ODA) to encourage the development of products for rare diseases or conditions ("orphan products"). The Act provided incentives to sponsors for developing products with orphan designation and established a grant program to fund studies of orphan products. Since its enactment in 1983, the ODA has been credited for bringing more than 590 orphan drugs to the market, inspiring the implementation of orphan legislation globally, and enabling the creation of other programs that extend existing knowledge of the natural history of rare diseases and stimulate the development of medical devices for children and patients with rare diseases. This chapter provides a brief overview of the main features and successes of 5 of the orphan incentive programs administered by the US Food and Drug Administration (FDA): the Orphan Drug Designation Program, the Humanitarian Use Device (HUD) Designation Program, the Orphan Products Clinical Trials Grants Program, the Pediatric Device Consortia (PDC) Grant Program, and the Orphan Products Natural History Grants Program.

Improving Investor-Investee Matches with Regulation: Evidence from the Orphan Drug Act & Global Biotechnology Industry

Venture capitalists (VCs) ideally like to invest in innovations at a nascent stage but this is inherently incorporated with huge risks (Ruhnka and Young 1991, Gompers 1995). Because it is difficult to value novel technologies at an early development stage, VCs may be herding into financing advanced-stage projects for which an archive of scientific knowledge and commercial performance are available that enables a correct valuation (Lerner 2009). A response to this market failure in investor-investee matches might be an institutional change that can steer investors towards supporting new innovations at an early stage, providing more information necessary to value young projects. Using the setting of the Orphan Drug Act (ODA) in the European Union (EU) enacted in 1999, we test these ideas in the fields of biotechnology using a difference in difference methodology and find that VCs are indeed more likely to invest in early-stage technologies in sub-fields disproportionately affected by ODA. In addition, we document that exit performances of VC-backed startups do not get worse as a result of VCs investing into early-stage innovations. Our results suggest that VCs are enabled to make fully-informed decisions as ODA provides some additional information on early-stage technologies. We conclude discussing the role of public policy in correcting market failure between investor-investee matches in the market for entrepreneurial finance.

Pharmaceutical expenditure on drugs for rare diseases in Canada: a historical (2007-13) and prospective (2014-18) MIDAS sales data analysis.

BackgroundHealth Canada has defined rare diseases as life-threatening, seriously debilitating, or serious chronic conditions affecting a very small number of patients (~1 in 2,000 persons). An estimated 9 % of Canadians suffer from a rare disease. Drugs treating rare diseases (DRDs) are also known as orphan drugs. While Canada is currently developing an orphan drug framework, in the United States (US), the Orphan Drug Act (ODA) of 1983 established incentives for the development of orphan drugs.This study measured total annual expenditure of orphan drugs in Canada (2007–13) and estimated future (2014–18) orphan drug expenditure.MethodsOrphan drugs approved by the US Food and Drug Administration (FDA) in the US were used as a proxy for the orphan drug landscape in Canada. Branded, orphan drugs approved by the FDA between 1983 through 2013 were identified (N = 356 unique products). Only US orphan drugs with the same orphan indication(s) approved in Canada were included in the analysis. Adjustment via an indication factoring was applied to products with both orphan and non-orphan indications using available data sources to isolate orphan-indication sales. The IMS Health MIDAS database of audited biopharmaceutical sales was utilized to measure total orphan drug expenditure, calculated annually from 2007–2013 and evaluated as a proportion of total annual pharmaceutical drug expenditure (adjusted to 2014 CAD).ResultsBetween 2007 and 2013, expenditure was measured for a final N = 147 orphan drugs. Orphan drug expenditure totaled $610.2 million (M) in 2007 and $1,100.0 M in 2013, representing 3.3– 5.6 % of total Canadian pharmaceutical drug expenditure in 2007–2013, respectively. Future trend analysis suggests orphan drug expenditure will remain under 6 % of total expenditure in 2014–18.ConclusionsWhile the number of available orphan drugs and associated expenditure increased over time, access remains an issue, and from the perspectives of society and equity, overall spending on orphan drugs is lower relative to the number of patients affected with an orphan disease in Canada. The overall budget impact of orphan drugs is small and fairly stable relative to total pharmaceutical expenditure. Concerns that growth in orphan drug expenditure may lead to unsustainable drug expenditure do not appear to be justified.

Novel treatments for rare rheumatologic disorders: analysis of the impact of 30years of the US orphan drug act.

BackgroundRare rheumatologic diseases are a heterogeneous group of conditions associated with high morbidity. As a whole group, rare rheumatologic diseases afflict millions of people demanding for effective therapies. Therefore, we analyzed the impact of the US Orphan Drug Act on the development of anti-rheumatic orphan drugs.MethodsAnalysis of the FDA database for orphan drug designations.ResultsIn the last three decades, out of 77 orphan drug designations, 14 orphan drug approvals were granted by the FDA for the treatment of rare rheumatologic disorders, i.e. juvenile idiopathic arthritis (N = 5), cryopyrin-associated periodic syndromes (N = 3), uveitis (N = 3), familial Mediterranean fever (N = 1), anti-neutrophil cytoplasmic antibody-associated vasculitis (N = 1), and xerostomia and keratoconjunctivitis sicca in Sjögren’s syndrome (N = 1). Mean time (standard deviation) from designation to approval was 3.9 (2.81) [range 1 … 12] years. Number of FDA-approved small molecules (N = 6, 43 %) and biologics (N = 8, 57 %) was comparable. Almost every fifth (19 %) orphan drug designation was withdrawn. Despite the rarity of conditions, 13/14 pivotal studies were randomized controlled trials.ConclusionsOrphan drug development is challenging: thirty years of US orphan drug act supported the development and FDA approval of 14 orphan drug programs with anti-rheumatic compounds for six rheumatologic diseases.

Novel Treatments for Rare Cancers: The U.S. Orphan Drug Act Is Delivering-A Cross-Sectional Analysis.

Rare cancers are a heterogeneous group of conditions with highly unmet medical needs. Although infrequent in individuals, rare cancers affect millions of people who deserve effective treatments. Therefore, we systematically analyzed the impact of the U.S. Orphan Drug Act of 1983 on delivery of novel treatments for rare cancers. Quantitative cross-sectional analysis was conducted on the U.S. Food and Drug Administration Orphan Drug Product database according to Strengthening the Reporting of Observational Studies in Epidemiology Statement criteria between 1983 and 2015. Since 1983, a total of 177 approvals have originated from 1,391 orphan drug designations to treat rare cancers, which represents 36% of all approvals within the U.S. orphan drug act (n = 492). Two compounds (1%) to treat rare cancer were withdrawn after approval. Median time from designation to approval was 2.49 years (interquartile range 1.13-4.64) and decreased significantly over time (p < .001, linear regression). Over the last decade, rare cancer treatments have been transformed from nonspecific cytotoxic agents toward targeted therapies, such as protein kinase inhibitors and monoclonal antibodies, representing the largest groups of innovative rare cancer treatments today. Most compounds were approved to treat solid tumors and hematological malignancies. The U.S. Orphan Drug Act and associated incentives, such as 7 years of marketing exclusivity, have fostered delivery of novel treatments for rare cancers. More than one-third of all orphan drug approvals address needs of patients suffering from rare cancers. Over the last decade, the understanding of tumorigenesis and genetic driver mutations in different tumor entities has produced innovative treatments, of which many were first approved within the U.S. Orphan Drug Act. Over the last 30 years, the U.S. Orphan Drug Act successfully delivered numerous novel treatments for rare cancers, of which some were subsequently used in other, nonorphan indications. The understanding of molecular mechanisms of diseases is directly connected to the search for novel therapies. The constant pursuit to translate basic research findings into clinical practice is a crucial prerequisite to address unmet medical needs in rare cancers, as in other rare diseases. Oncological drug development proves to be a major player in overall orphan drug research, displayed by more than one-third of all U.S. Food and Drug Administration-approved orphan drugs with oncological indications.

Pressure for drug development in lysosomal storage disorders - a quantitative analysis thirty years beyond the US orphan drug act.

BackgroundLysosomal storage disorders are a heterogeneous group of approximately 50 monogenically inherited orphan conditions. A defect leads to the storage of complex molecules in the lysosome, and patients develop a complex multisystemic phenotype of high morbidity often associated with premature death. More than 30 years ago the Orphan Drug Act of 1983 passed the United States legislation intended to facilitate the development of drugs for rare disorders.We directed our efforts in assessing which lysosomal diseases had drug development pressure and what distinguished those with successful development and approvals from diseases not treated or without orphan drug designation.MethodsAnalysis of the FDA database for orphan drug designations through descriptive and comparative statistics.ResultsBetween 1983 and 2013, fourteen drugs for seven conditions received FDA approval. Overall, orphan drug status was designated 70 times for 20 conditions. Approved therapies were enzyme replacement therapies (N = 10), substrate reduction therapies (N = 1), small molecules facilitating lysosomal substrate transportation (N = 3). FDA approval was significantly associated with a disease prevalence higher than 0.5/100,000 (p = 0.00742) and clinical development programs that did not require a primary neurological endpoint (p = 0.00059). Orphan drug status was designated for enzymes, modified enzymes, fusion proteins, chemical chaperones, small molecules leading to substrate reduction, or facilitating subcellular substrate transport, stem cells as well as gene therapies.ConclusionsDrug development focused on more common diseases. Primarily neurological diseases were neglected. Small clinical trials with either somatic or biomarker endpoints were successful. Enzyme replacement therapy was the most successful technology. Four factors played a key role in successful orphan drug development or orphan drug designations: 1) prevalence of disease 2) endpoints 3) regulatory precedent, and 4) technology platform. Successful development seeded further innovation.

The Budget Impact of Orphan Drugs in the U.S.: A 2007-2013 MIDAS Sales Data Analysis

Introduction: The Orphan Drug Act (ODA) of 1983 established incentives for the development of drugs that treat rare or orphan diseases. The ODA targets therapies for diseases affecting fewer than 200,000 patients in the US. As a consequence, orphan drug development was stimulated and therapies have been developed to treat a variety of previously underserved conditions including acute myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, myelodysplastic syndromes, Gaucher disease and Hunter syndrome. Between 1973 to 1983, prior to the ODA, less than 10 drugs for orphan conditions were available to patients, while in 2013 the FDA website listed more than 400 approved orphan drugs (this includes both new molecular entities and supplemental applications/indications). Due to the perceived high therapy costs and therefore potential impact on payer’s drug budgets, orphan drugs are facing increasing scrutiny from payers. The objective of this study was to estimate the total annual expenditures on orphan drugs in the US from 2007 to 2013, and to evaluate orphan drug expenditures as a percentage of total pharmaceutical expenditures.Methods: A list of drugs which have been approved by the FDA and given orphan status in the US since the establishment of the ODA through the end of 2013 was generated from the US FDA Orphan Drug Product designation website (N=366 unique products). Only branded products (N=357) were considered in this analysis. The IMS MIDAS database, the gold standard for audited biopharmaceutical sales, was used to assess orphan drug and total drug expenditures. The MIDAS database integrates and extends the IMS National Prescription Audits, which detail estimated sales by product and therapy class through retail and non-retail channels at the unit of the product pack level. The analysis focused on orphan drugs with expenditures measured between 2007 and 2013 in the MIDAS database. Only products with a single orphan indication or with multiple indications which were all orphan were included in the analysis (N=303). Total orphan drug expenditures were calculated annually from 2007 to 2013 and further reported as a proportion of total annual pharmaceutical drug expenditures. All expenditures were adjusted to 2014 USD using the Bureau of Economic Analysis GDP deflator. Expenditures for orphan drugs with cancer indications were evaluated as a subset of all orphan drugs.Results: Between 2007 and 2013, expenditures were measured for a final N=266 branded orphan drugs in the MIDAS database; 37 out of 303 were either not present or had no sales in MIDAS. Orphan drug expenditures totaled $15.0 billion (B) in 2007 and $25.6B in 2013, representing 4.8% to 7.6% of total U.S. pharmaceutical drug expenditures in 2007 and 2013, respectively (Figure 1). There were 74 (27.8%) orphan drugs identified with an orphan cancer indication with expenditures representing 26.7% (2007) and 34.8% (2013) of total orphan drug expenditures. Over the same period (2007–2013), a total of 145 orphan drugs were granted approval (both new molecular entities and supplemental applications/indications).Conclusions: Although the ODA has led to an increase in the number of approved orphan drugs and the annual expenditures on orphan drugs, the overall budget impact of orphan drugs is relatively small and has remained fairly stable as a proportion of total pharmaceutical expenditures. Concerns that growth in orphan drug expenditures may lead to unsustainable drug expenditures do not appear to be justified. [Display omitted] DisclosuresDivino:IMS Health: Employment. Dekoven:IMS Health: Employment. Wang:MKTXS: Employment. Kleinrock:IMS Health: Employment. Harvey:Celgene, Millennium, Onyx and Novartis: Research Funding. Wade:IMS Health: Employment. Kaura:Celgene: Employment, Equity Ownership.

Angioedema is not just ‘deep urticaria’ but an entity of its own

Angioedema is not just ‘deep urticaria’ but an entity of its own

PHP30 The Bittersweet Success of Orphan Drugs

Legislation such as the Orphan Drug Act (ODA) in the United States (US), and Regulation 141/2000 in the European Union (EU) have been successful in stimulating research and development and supporting regulatory approval of orphan drugs that would not have otherwise been commercially viable. This success, however, has been bittersweet. While increasing numbers of patients with rare diseases have gained access to potentially life-saving or life-extending treatments, decision makers have struggled to mitigate the impact of expensive orphan drugs on overall drug and healthcare budgets. The objective of this study was two-fold; 1) to explore the impact of orphan drug legislation on patient access to drugs for rare diseases in the US and EU, and 2) to quantify the impact of costs associated with orphan drugs on overall drug and healthcare budgets in the US and EU. An exhaustive literature search was performed to identify orphan drugs which are currently funded in the US or EU, determine the prevalence of orphan diseases treated by these drugs, identify the costs associated with these drugs, and explore the impact of these costs on overall drug and healthcare budgets. Literature searches were conducted using various search engines, including PubMed, Google, and Google Scholar. Legislative initiatives directed at drugs for rare diseases in the US and EU have resulted in the development and funding of an unprecedented number of drugs for rare diseases. The recent approval of a multitude of new drugs for rare diseases in the US and EU has led to notable increases in overall drug and healthcare budgets. Reimbursement and patient access for orphan drugs will become increasingly more challenging as decision makers become more prohibitive in their approval of new and expensive drugs. Criterion for the reimbursement of drugs for rare diseases needs to be clearly established and communicated.

What the Orphan Drug Act Has Done Lately for Children With Rare Diseases: A 10-Year Analysis

The 1983 US Orphan Drug Act (ODA) provided incentives to stimulate treatment product development for patients with rare disease. This article highlights a decade of ODA contributions to this goal for children with RDs. An internal US Food and Drug Administration database was the information source for orphan designations, marketing approvals, and prevalence numbers for 2000 to 2009. Product categorization was based on the disease age of onset for which they received designation. Category 1 products were for diseases with onset exclusively in Childhood; Category 2 products were for diseases with onset at any age; and Category 3 products were for diseases with adult onset only. Disease prevalence distributions were analyzed by using population intervals of 20 000. From 2000 to 2009, 1138 orphan drugs were designated and 148 received marketing approval, of which 38 (26%) were for pediatric diseases. The proportion of approvals for pediatric products increased from 17.5% (10 of 57) in the first half of the decade, to 30.8% (28 of 91) in the second. More products received designation and marketing approval for pediatric diseases with prevalence numbers fewer than 20 000 than for any other prevalence subgroup. The median disease prevalence for all pediatric orphan designations that received marketing approval was 8972. Among the pediatric orphan drug approvals categorized by therapeutic class, the endocrine/metabolic drugs had the largest representation (39%). The ODA incentives have led to increased product availability for RDs overall, with an increasing number of marketing approvals for children this past decade.

Orphanage at the FDA

In the late 1970s and early 1980s, social and political forces gave birth to a new movement to serve the needs of people with rare diseases, a movement that has only accelerated with the penetrance of internet connectivity. The FDA's Office of Orphan Products Development (OOPD) was established in 1982 to promote the development of products that demonstrate promise for the diagnosis, prevention, and/or treatment of rare diseases or conditions. Additional governmental responses included passage of the 1983 Orphan Drug Act (ODA) as well as subsequent legislation for medical devices. This article describes how OOPD assists in the development of orphan products (drugs, biologics, medical devices, and medical foods) for patients with rare diseases. The 40 clinicians, pharmacists, scientists, engineers, and others who perform OOPD's mission activities are broadly committed to providing useful new therapies to people with rare diseases. However, OOPD does not actually decide what products (drugs, biologics devices, and medical foods) are licensed for marketing and which applications are denied. Rather, OOPD has three key functions: certifying that indeed a product has bona fide promise for use in a rare disease, granting funds for the development of such products and advocating with stakeholders for the creation of new therapies in rare disease therapies.

The Impact of the Orphan Drug Act on the Development and Advancement of Neurological Products for Rare Diseases: A Descriptive Review

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.

R&D policy, agency costs and innovation in personalized medicine

The Orphan Drug Act (ODA) was designed to spur the development of drugs for rare diseases. In principle, its design also incentivizes pharmaceutical firms to develop drugs for “rare” subdivisions of more prevalent diseases. I find that in response to this incentive, firms develop drugs for ODA-qualifying subdivisions of non-rare diseases. The impact in these tailored drug markets represents half of the total R&D response to the ODA. I also find that 10-percent of the innovation in subdivided disease drugs induced by the ODA would have been conducted without the policy. While modest in size, this inefficiency suggests that agency problems should be considered when designing innovation policy.

Market incentives and pharmaceutical innovation

I study the impact of the Orphan Drug Act (ODA), which established tax incentives for rare disease drug development. I examine the flow of new clinical drug trials for a large set of rare diseases. Among more prevalent rare diseases, the ODA led to a significant and sustained increase in new trials. The impact for less prevalent rare diseases was limited to an increase in the stock of drugs. Tax credits can stimulate R&D; yet because they leave revenue margins unaffected, tax credits appear to have a more limited impact on private innovation in markets with smaller revenue potential.

Editorial: Drug development for neglected diseases: a public health challenge

More than 7000 diseases of humans are classified as orphan diseases [Bundesministerium fur Bildung und Forschung (BMBF) 2005]. For this classification, a disease must not exceed a prevalence of 1.1 patients (Australia) to 7.5 patients in 10 000 people (USA). In the European Union, the figure is five patients in 10 000 people (OrphaNet 2006). For small patient populations such as these, drug development is economically difficult. In 1983, the U.S. Congress adopted the first law to foster research and development for drugs for orphan diseases. The U.S. Orphan Drug Act (ODA) contains economic stimuli for the pharmaceutical industry such as market exclusivity or registration fee waivers. Similar legislation followed in Japan (1993), Australia (1998) and in the European Union (2000) (OrphaNet 2006). Judging from the number of orphan drugs marketed after the adoption of these regulations, it proved successful. Between 1983 and 2002, 232 orphan products in the USA received FDA marketing approval, compared with ten products in the 10 years preceding the ODA (Haffner et al. 2002). In the European Union, 22 products received marketing authorization between April 2000 and April 2005, and >260 products were designated as orphan products, relating to >200 rare conditions (EMEA/COMP 2005). The existing incentives, however, may still be insufficient for many firms to launch research for orphan drugs (Anonymous 2005).

A journey of hope: lessons learned from studies on rare diseases and orphan drugs

Rare diseases are frequently life-threatening or chronically debilitating and the impact on the quality of life of affected patients and their family members is thus significant. However, drug development for these conditions has been limited by a lack of understanding of the underlying mechanisms of disease and the relative unavailability of subjects for clinical trials, as well as the prohibitive cost of investing in a novel pharmaceutical agent with poor market potential. Nevertheless, the introduction of Orphan Drug legislations has provided important incentives for the development of orphan drugs (i.e. drugs that have been abandoned or 'orphaned' by major drug companies). Moreover, recent studies on rare diseases, including inherited immunodeficiencies and metabolic disorders, have served not only to alleviate the plight of patients with rare diseases, but also yielded valuable information on biological processes of relevance for other, more common conditions. These lessons, along with the crucial importance of cooperation between academic institutions, pharmaceutical companies, patient advocacy groups and society in the elucidation of rare diseases, are highlighted in the present review.

Advance price or purchase commitments to create markets for treatments for diseases of poverty: lessons from three policies.

New drugs and vaccines are needed for tackling diseases of poverty in low- and middle-income countries. The lack of effective demand or market for these products translates into insufficient investment being made in research and development to meet the need for them. Many have advocated cost-reducing (push) and market-enhancing (pull) incentives to tackle this problem. Advance price or purchase commitments (APPCs) funded by international agencies and governments offer one way forward. This paper looks at design issues for APPCs for drugs and vaccines for diseases of poverty drawing on experience and lessons from three case studies: the introduction of the meningitis C vaccine in the United Kingdom; the Orphan Drug Act (ODA) in the United States of America (US); and the newly legislated US Project BioShield for bioterrorist interventions. Our key conclusion is that that APPCs have the potential to be a powerful tool and should be tried. The correct structure and design may only be determined through the process of taking action to set one up.