US Orphan Drug Research Articles

Orphan Drug Development Policies in India and the United States: A Comparison

Abstract: Background: A pharmacological agent known as an orphan drug was created to address rare or orphan diseases. The Food and Drug Administration (FDA) claims that the Orphan Drug Act has certainly encouraged the development of treatments for rare diseases. The Orphan Drug Act was passed in the United States in 1983 to encourage pharmaceutical companies to develop treatments for rare diseases. Global sales of orphan drugs are anticipated to increase at a Compound Annual Growth Rate (CAGR) of 12.3% from 2019 to 2024, which is roughly double the rate anticipated for the non-orphan drug industry. India has between 72 and 96 million people who are affected by rare diseases. There are no specific orphan drug laws in India. The Ministry of Health and Family Welfare of India established a National Policy for the Treatment of Rare Diseases in July 2017 (NPTRD). However, there were challenges to the execution of the policy. The Orphan Drug Act, which was passed on January 4, 1983, gave orphan medications legal status in the United States. The lack of orphan drug regulation hurts the Indian pharmaceutical businesses' ability to thrive economically. Contrarily, the US's orphan drug regulations have been effective in bringing therapies to people with rare disorders. The assessment of the scope and impact of orphan diseases, as well as a widespread awareness campaign about orphan diseases, are urgently needed in the current situation. Orphan drug development requires strong policies and initiatives from both public and private institutions. Materials and Methods: This review article is based on the information collected from various sources from FDA and NPTRD and the articles mentioned. Results: The different guidelines and regulations for the development and manufacture of orphan pharmaceuticals should be put into place to ensure that orphan diseases get the necessary treatment and care. Conclusion: The FDA regularly updates and the Orphan Drug Act provides direction for the overall rules and regulations in the United States. In India, being a semi-regulated market, there are no such specific rules and regulations regarding development. The National Policy for Rare Disease in India 2021 helps as a guidance document regarding the policies related to orphan drugs in India. Keywords: Orphan Drugs, Orphan diseases, Rare diseases, Initiative, Treatment.

Expensive Drug Prices for Rare Cancers: Are Patients Truly Benefitting?

Cancer medicines comprise the largest proportion of expensive drugs for rare diseases (EDRDs). The US Orphan Drug Act (ODA) (Office of Inspector General, Department of Health and Human Services 2001) encourages pharmaceutical manufacturers to develop medicines for rare diseases through a range of financial incentives, which has shifted the development of cancer medicines to rare cancer subtypes. Although certain medicines approved through the ODA have revolutionized cancer treatment, only half demonstrate added therapeutic benefit compared to existing alternatives. Canadian regulators should ensure that cancer medicines that receive fast-track approval through the Health Canada Notice of Compliance with conditions offer benefit to Canadian patients. Furthermore, payers might engage in methods for reassessment and renegotiations over the medicines' lifespan.

Evaluation of clinical trials done for orphan drugs versus nonorphan drugs in infectious diseasesan eleven year analysis [2010-2020

The 1983 US Orphan Drug Act provided impetus for the development of new therapies for rare diseases. Several studies focused on the number of orphan designations over time. However, very few focused on clinical trials that lead to their approval, particularly for infectious diseases. All new drug approvals (orphan and non-orphan) by the US Food and Drug Administration (FDA) from January 2010 to December 31, 2020, were identified and details of approvals were taken from the US-FDA labels and summary reports for each drug. The pivotal trials for each were characterized based on their design. We tested the association of the type of drug approval with respect to the characteristics of trial using Chi-square test and generated crude odds ratios with 95% confidence intervals. From the total 1122 drugs approved, 84 were for infectious diseases, of which 18 were orphan drugs and 66 were nonorphan. A total of 35 pivotal trials supported 18 orphan drug approvals, while 115 pivotal trials supported 66 nonorphan drugs. The median number of participants enrolled/trial for orphan drugs was 89, while for nonorphan drugs, it was 452 (P < 0.0001). Blinding was done for 13/35 (37%) orphan drugs versus 69/115 (60%) nonorphan drugs (P = 0.029); randomization was done for 15/35 (42%) orphan drugs versus 100/115 (87%) nonorphan drugs (P < 0.0001) and 20/35 (57%) of the orphan drugs got approval in phase II versus 8/115 (6%) of nonorphan drugs (P < 0.00001). A significant number of orphan drugs get approval based on early phase, nonrandomized, and unblinded with a smaller sample size as compared to nonorphan drugs.

Orphan drug development in alpha-1 antitypsin deficiency

Alpha-1 antitrypsin deficiency (AATD, OMIM #613490) is a rare metabolic disorder affecting lungs and liver. The purpose of this study is to assess the impact of the US orphan drug act on AATD by providing a quantitative clinical-regulatory insight into the status of FDA orphan drug approvals and designations for compounds intended to treat AATD. This is across-sectional analysis of the FDA database for orphan drug designations. Primary endpoint: orphan drug approvals. Secondary endpoint: orphan drug designations by the FDA. Close of database was 16 July 2021. STROBE criteria were respected. Primary outcome: one compound, alpha-1-proteinase inhibitor (human) was approved as an orphan drug in 1987 with market exclusivity until 1994. Secondary outcome: sixteen compounds received FDA orphan drug designation including protein, anti-inflammatory, mucolytic, gene, or cell therapy. Drug development activities in AATD were comparable to other rare conditions and led to the FDA-approval of one compound, based on a relatively simple technological platform. The current unmet medical need to be addressed are extrapulmonary manifestations, in this case the AATD-associated liver disease. Orphan drug development is actually focusing on (1) diversified recombinant AAT production platforms, and (2) innovative gene therapies, which may encompass a more holistic therapeutic approach.

HTA24 Orphan Drugs: What Is the Impact of Special Provisions in Value Assessment?

Favourable regulatory, evidence evaluation and tax regulations for orphan drugs (ODs) in the US and Europe aim to encourage OD development to fill clinical unmet needs and facilitate access to ODs. Manufacturers have responded positively to these incentives, measured by the number of OD launches since 1982 – when the US Orphan Drug Act became the first OD law in the world. More recently, HTA agencies and US payers have begun to expect evidence as solid for ODs as they expect for non-ODs (NODs). In this research, we test the hypothesis that OD provisions in value assessment confer manufacturer benefits in HTA and pricing.

Regulatory environment for novel therapeutic development in mitochondrial diseases.

At present, there is just one approved therapy for patients with mitochondrial diseases in Europe, another in Japan, and none in the United States. These facts reveal an important and significant unmet need for approved therapies for these debilitating and often fatal disorders. To fill this need, it is critical for clinicians and drug developers to work closely with regulatory agencies. In the United States, mitochondrial disease patients and clinicians, the United Mitochondrial Disease Foundation, and pharmaceutical industry members have engaged with the Food and Drug Administration to educate each other about these complex and heterogeneous diseases and about regulatory requirements to obtain approvals for novel therapies. Clinical development of therapies for rare diseases has been facilitated by the 1983 US Orphan Drug Act (ODA) and similar legislation in Japan and the European Union. Further legislation and regulatory guidance have expanded and refined regulatory flexibility. While regulatory and financial incentives of the ODA have augmented involvement of pharmaceutical companies, clinicians, with patient advocacy groups and industry, need to conduct natural history studies, develop clinical outcome measures, and identify potential supportive surrogate endpoints predictive of clinical benefit, which together are critical foundations for clinical trials. Thus, the regulatory environment for novel therapeutic development is conducive and offers flexibility for mitochondrial diseases. Nevertheless, flexibility does not mean lower standards, as well-controlled rigorous clinical trials of high quality are still required to establish the efficacy of potential therapies and to obtain regulatory agency approvals for their commercial use. This process is illustrated through the authors' ongoing efforts to develop therapy for thymidine kinase 2 deficiency.

Market Exclusivity for Drugs with Multiple Orphan Approvals (1983-2017) and Associated Budget Impact in the US.

The Orphan Drug Act extends exclusivity of branded drugs by 7years for each rare disease approval. By extending market exclusivity, manufacturers can forestall generic competition. We determined the prevalence of drugs with multiple orphan approvals, the duration for which manufacturers are able to maintain exclusivity using this mechanism, and the budget impact of these additional exclusivity periods on US spending on orphan drugs. We analyzed a retrospective cohort of US orphan drug approvals filed between 1983 and 2017. Drug costs throughout this time period were measured using IQVIA claims data. We estimated additional years of exclusivity per drug per orphan approval using mixed-effects negative binomial regression. The budget impact analyzed potential cost-savings for exclusivity periods greater than 7years after the initial orphan approval based on potential price reductions from the introduction of biosimilar/generic competition. A total of 432 branded drugs were approved for 615 orphan indications, of which 108 had multiple indications. Market exclusivity, beyond the initial 7years, increased by 4.7years with two orphan approvals, and there were 3.1-, 2.7-, and 2.9-year extensions for three, four, and five approvals, respectively (p < 0.05). Drugs with five approvals averaged 13.4 additional years of exclusivity. Sixteen drugs had exclusivity periods extending at least 1 decade beyond the original exclusivity period. The potential budget impact of additional exclusivity was estimated at US$591 billion for 7years following the end of the first approval. Multiple blockbuster drugs have received exclusivity of > 10years through the Orphan Drug Act, thereby delaying rare disease cohorts' access to generic/biosimilar equivalents.

Tepotinib: First Approval.

Tepotinib (Tepmetko™, Merck) is a MET tyrosine kinase inhibitor being developed for the treatment of solid tumours. In quarter three of 2019 tepotinib was granted breakthrough therapy status by the US FDA and orphan drug designation by the Japanese Ministry of Health, Labour and Welfare for the treatment of non-small cell lung cancer harbouring MET alterations, and in March 2020 was approved for use in Japan in this indication. This article summarizes the milestones in the development of tepotinib leading to this first approval.

Affordability and availability of off-patent drugs in the United States—the case for importing from abroad: observational study

ObjectivesTo evaluate whether off-patent prescription drugs at risk of sudden price increases or shortages in the United States are available from independent manufacturers approved in other well regulated settings around...

Orphans in the Market: The History of Orphan Drug Policy.

SummaryThis paper examines the history of orphan drug policy, from the emergence of ‘orphans’ in the American pharmaceutical market in the 1960s, through the debates and agitations that resulted in the passage of the US Orphan Drug Act of 1983, to attempts in the 1990s to prevent abuse of that Act and restore its original intentions. Although an increased number of drugs for rare diseases have since been developed and marketed, the extremely high price of some such drugs is considered a major public health issue internationally. The present paper traces the origins of this issue to the market-based approach to resolving the problem of orphan drugs embodied in the 1983 Act. The paper also makes visible an alternative trajectory that existed for a while in the United Kingdom but was eventually abandoned in order to help the biotechnology industry grow in the context of an increasingly integrated European drug market.

History of Orphan Drug Regulation-United States and Beyond.

The US Orphan Drug Act, passed in 1982, was the first orphan drug legislation in the world. It is a law based on economic incentives making it financially possible for pharmaceutical firms to develop products for small patient populations. Since passage, many additional countries have developed orphan drug programs and many pharmaceutical firms have developed around the orphan program. Today, more than 500 drugs for rare diseases have been developed in the United States.

Thirty Years of Orphan Drug Legislation and the Development of Drugs to Treat Rare Seizure Conditions: A Cross Sectional Analysis.

BackgroundEpilepsy is a serious chronic health condition with a high morbidity impairing the life of patients and afflicted families. Many epileptic conditions, especially those affecting children, are rare disorders generating an urgent medical need for more efficacious therapy options. Therefore, we assessed the output of the US and European orphan drug legislations.MethodsQuantitative analysis of the FDA and EMA databases for orphan drug designations according to STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) criteria.ResultsWithin the US Orphan Drug Act 40 designations were granted delivering nine approvals, i.e. clobazam, diazepam viscous solution for rectal administration, felbamate, fosphenytoin, lamotrigine, repository corticotropin, rufinamide, topiramate, and vigabatrin. Since 2000 the EMA granted six orphan drug designations whereof two compounds were approved, i.e. rufinamide and stiripentol. In the US, two orphan drug designations were withdrawn. Orphan drugs were approved for conditions including Lennox-Gastaut syndrome, infantile spasms, Dravet syndrome, and status epilepticus. Comparing time to approval for rufinamide, which was approved in the US and the EU to treat rare seizure conditions, the process seems faster in the EU (2.2 years) than in the US (4.3 years).ConclusionOrphan drug development in the US and in the EU delivered only few molecular entities to treat rare seizure disorders. The development programs focused on already approved antiepileptic drugs or alternative pharmaceutical formulations. Most orphan drugs approved in the US are not approved in the EU to treat rare seizures although some were introduced after 2000 when the EU adopted the Orphan Drug Regulation.

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.

Some Numbers behind Canada’s Decision to Adopt an Orphan Drug Policy: US Orphan Drug Approvals in Canada, 1997–2012

We examined whether access to US-approved orphan drugs in Canada has changed between 1997 (when Canada chose not to adopt an orphan drug policy) and 2012 (when Canada reversed its policy decision). Specifically, we looked at two dimensions of access to US-approved orphan drugs in Canada: (1) regulatory access; and (2) temporal access. Whereas only 63% of US-approved orphan drugs were granted regulatory approval in 1997, we found that regulatory access to US-approved orphan drugs in Canada increased to 74% between 1997 and 2012. However, temporal access to orphan drugs is slower in Canada: in a head-on comparison of 40 matched drugs, only two were submitted and four were approved first in Canada; moreover, the mean review time in Canada (423 days) was longer than that in the US (mean = 341 days), a statistically significant difference (t[39] = 2.04, p = 0.048). These results raise questions about what motivated Canada's apparent shift in orphan drug policy.

Abstract 4199: Developing therapies for rare tumors: Using mouse models of malignant peripheral nerve sheath tumors to complement rare human samples in drug screens

Abstract Rare cancers are defined by the US Orphan Drug Act as affecting &amp;lt;200,000 patients in the US. For patients with these cancers, there may be an urgent need for new therapies; however, these rare cancers present challenges to drug development. Because of the small number of patients, the cancers are not well characterized, the molecular mechanisms may not be well-understood, and there may not be adequate model systems available for research and drug development. The Rare Tumors Initiative in the Intramural Research Program at the National Cancer Institute is focusing on overcoming hurdles in rare tumor research by developing new approaches to treat malignant peripheral nerve sheath tumors (MPNST). MPNSTs occur in younger adults with an incidence of 1 in 100,000, with a higher incidence in patients with Neurofibromatosis type 1. Due to a limited number of high quality human MPNST tumor lines, drug testing has been challenging both in vitro and in vivo. A genetically engineered mouse model carrying mutations in Nf1 and Trp53 develops MPNST spontaneously starting around 3 months of age. We have generated tumor lines from over 30 independent mouse MPNSTs, from different sexes and genetic backgrounds that we are using to test drugs in combination with available human MPNST lines. We find good concordance between the mouse and human MPNST lines in response to drugs. Furthermore, although the MPNST lines show good dose response and high maximum response to many targeted compounds, the concentrations of drug required to achieve inhibition is often high, suggesting that one of the difficulties in developing MPNST therapy is the inherent resistance of MPNST cells to drug inhibition. We will present results of ongoing drug screens in panels of mouse and human MPNST cell lines, using drugs that are in different phases of clinical trials or approved for other diseases. Citation Format: Karlyne M. Reilly, Robert G. Tuskan, Brigitte C. Widemann. Developing therapies for rare tumors: Using mouse models of malignant peripheral nerve sheath tumors to complement rare human samples in drug screens. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4199. doi:10.1158/1538-7445.AM2015-4199

PSY77 - Timing of eu5 & US Orphan Drug approvals and PRMA between 2009 and 2013

PSY77 - Timing of eu5 & US Orphan Drug approvals and PRMA between 2009 and 2013

Orphan drug incentives in the pharmacogenomic context: policy responses in the US and Canada.

Advances in pharmacogenomic research and increasing industry interest in personalized medicine have important implications for the way that orphan drug policies are interpreted and applied. Concerns have been raised about the potential impact of pharmacogenomics and new genomic technologies on our understanding of how disease categories are delineated, and subsequently, how the concept of rare disease should be defined for the purposes of orphan drug policies. This article considers whether orphan drug legislation can be drafted in a way that will maximize benefits and minimize concerns relating to the impact of pharmacogenomics on orphan drug research and development. After reviewing the issues that may arise at the intersection of orphan drug policies and pharmacogenomics, this article will discuss the potential impact of pharmacogenomics at two critical points: orphan designation and approval of the drug product. At each of these points, the relevant aspects of current US orphan drug legislation are examined, focusing on the extent to which recent amendments may address concerns that have been raised previously. This analysis will then provide the foundation for a critical review and recommendations regarding the proposed new Canadian orphan drug framework.

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.

A 30-year retrospective: National Organization for Rare Disorders, the Orphan Drug Act, and the role of rare disease patient advocacy groups

A 30-year retrospective: National Organization for Rare Disorders, the Orphan Drug Act, and the role of rare disease patient advocacy groups Mary Dunkle National Organization for Rare Disorders, Danbury, CT, USA Abstract: This 30-year retrospective looks at the history of the US Orphan Drug Act and how it originally came to be enacted, with particular emphasis on the role of patient advocacy organizations. The article explores how rare-disease patient advocacy groups learned to work with government partners in the National Institutes of Health and US Food and Drug Administration, members of Congress, and the media to promote their cause. It also discusses their awakening to the value of collaboration, which led to the formation of an umbrella organization to represent their shared interests. Milestones over the years are briefly discussed, and current areas of focus for rare disease patient organizations &ndash; most notably, globalization &ndash; are also examined. Keywords: rare diseases, orphan products, NORD, Rare Disease Day, global patient communities, EURORDIS, NZORD, TFORD, CORD, rare disease research

The Pharmaceutical Market’s Adverse Effects

The Pharmaceutical Market’s Adverse Effects