Rare Disease Drug Development Research Articles

Cross-sector sponsorship of research in eosinophilic esophagitis: A collaborative model for rational drug development in rare diseases

Like many rare diseases, eosinophilic esophagitis (EoE) is a poorly understood disorder, and assessment tools to accurately determine disease activity, remission, and natural history have long been inadequate. Clinical outcome end points able to assess the effectiveness of candidate therapeutic agents in clinical trials have been a particular deficiency and are urgently needed. With no approved therapy available to patients and with the prevalence of EoE on the increase, collaborative approaches to drug development are becoming ever more important. We describe a collaborative effort mobilized across institutions, including both the public and private sectors, that was initiated within the past 18 months expressly to address the need for further clinical research into the cause and treatment of EoE. Collaborators include the North American Society of Pediatric Gastroenterology, Hepatology and Nutrition; the International Gastrointestinal Eosinophilic Researchers; and the US Food and Drug Administration. This effort has resulted in the elucidation of several parameters essential for effective EoE registration trials, including the need for clinically meaningful end points that measure changes in clinical symptoms in addition to the assessment of intraepithelial mucosal eosinophilia. The development and use of biomarkers, particularly in early-phase drug development, have become an important focus for investigations that might reduce clinical reliance on serial invasive monitoring. The concerted efforts described here to develop rational therapeutics and drug development paradigms in EoE also appear to provide a model for effective collaboration in the context of drug development for rare diseases and perhaps more generally for public health initiatives.

Rare diseases and orphan drugs

Rare diseases affect, by definition, only a small number of people. This article investigates how drug development for rare diseases can provide attractive opportunities for biopharmaceutical industries.

New NIH Center to Streamline Translational Science

Though NCATS is a new NIH center, it will primarily be home to programs and efforts that already operate elsewhere within NIH. (A complete list of NCATS's components can be found on the NCATS website.) “They have been reorganized into this new center essentially to create some new adjacencies and improve interaction,” says Insel.The only new NCATS entity is the newly funded Cures Acceleration Network (CAN), set to launch with a modest $10 million budget. CAN is intended to advance the development of “high need cures,” particularly in areas that private companies are unlikely to pursue.The first priority on NCATS's agenda is to find a permanent director to guide the center's 250 person team. A portion of this group will be devoted to grant review and overseeing administration of the center's clinical translational science awards (CTSA program) that fund about 60 research sites across the company with grants totaling nearly $500 million.A sizable group of about 140 people within NCATS will do hands-on intramural research within NIH, including small-molecule screening and drug development for rare diseases. “However, most of those projects are collaborative with external scientists both in academia and industry,” Insel explains. One example includes the TRND team, which is working with scientists at various external sites to find new treatments for sickle cell anemia, CLL, Neimann-Pick disease, and other disease targets.“An effort like NCATS, which is fundamentally focused on innovation, is going to serve both basic and more applied translational science,” adds Insel. “What we hope to do is blur or bridge the division between the two for the benefit of all—it's a great opportunity.”

New opportunity for orphan drug development in Japan: Early exploratory clinical trial bases promote drug translation from basic studies to clinical application

In Japan, although orphan drug legislation has been established in 1993 to encourage drug research and development (R&D) for intractable and rare diseases, nearly half of the orphan drugs in the Japanese market originated from the European Union (EU) or the United States of America (USA). Availability of orphan drugs for intractable and rare diseases is compounded by the "drug lag" phenomenon, which is mainly caused by the imperfect clinical trial environment in Japan. In recent years, the Japanese government paid great attention to development of innovative drugs and medical devices which originated from Japan. With financial support and institutional guarantees from government, the project of "Early Exploratory Clinical Trial Bases for Specific Research Areas" was launched in 2011 and 5 institutions were selected as the national early exploratory clinical trial bases for specific research areas including cancer, cerebral and cardiovascular diseases, neuropsychiatric disorders, and immunological intractable diseases. The early exploratory clinical trial bases offer a new opportunity for drug development for immunological and neuropsychiatric intractable diseases, thereby promoting orphan drug translation from basic studies to clinical use.

Orphan drugs in oncology

SincetheEMA/EuropeanMedicinesAgencyhasimplementedaregulationintend-ing to stimulate the developmentof drugs for rare diseases in 2000, 858 drugs havereceived Orphan Drug Designations, but only 62 drugs have yet received MarketingAuthorisation as an “orphan drug”. To benefit from the incentives (reduced fees formarketing-authorisationapplicationsandprotectionfrommarketcompetition),com-panies intending to develop an orphan medicine must submit an application to theEuropeanMedicinesAgencyrequesting’orphandesignation’fortheirmedicine. Theapplication is evaluated by the Agency’sCommittee for Orphan Medicinal Products(COMP), which provides its opinion on whether or not the medicine qualifies as anorphanmedicine for the treatment, preventionor diagnosis of a rare disease, definedas a condition affecting no more than 5 in 10,000 people in the EU. If the COMPissuesa positiveopinion,theEMA maythengrantthemedicineorphanstatus: allofthem registered in the Register of designated Orphan Medicinal Products [1].Even though a wide variety of diseases fulfil this criterion, the largest group(45.2%) for which the COMP has adopted a positive opinion as well as of the 62drugs finally having received marketing authorisation (35.5)% were for oncologytreatments [2]. By April 2011, 21 oncologic drugs (between 1 and 5 per year) havebeenapprovedasorphandrugs(seeTable1),someofthemformorethanoneindica-tion. According to industry-forecasts, the number of designations will “continue toincrease exponentially” [3] within the next months and years and consequently willthe numberof successful marketing authorisations.While the regulationfor orphandrugs, originallyintendedto providea favourableeconomic environment for the development of drugs for which either no marketor a too fragmented markets for the generation of adequate return on investmentexist, is euphorically discussed in pharma-fora and at biotech-conferences, health

Huntington's disease out of the closet?

In her Art of Medicine essay in The Lancet today, Alice Wexler 1 Wexler A Stigma, history, and Huntington's disease. Lancet. 2010; (published online June 30.)https://doi.org/10.1016/S0140-6736(10)60957-9 Summary Full Text Full Text PDF PubMed Scopus (32) Google Scholar recounts the stigma faced by those with Huntington's disease, a cruelly progressive and incurable neurodegenerative condition that usually (not invariably) presents in mid-life. The disease is inherited as an autosomal dominant trait so that children of a parent with Huntington's disease are all at risk, with each having a 50% chance of developing the disease if they live a normal lifespan. The stigma of Huntington's disease, therefore, attaches to those who are at risk as well as to those with symptoms. Stigma, history, and Huntington's diseaseUntil my mother was diagnosed with Huntington's disease—a hereditary degenerative neurological and psychiatric disorder characterised by chorea, cognitive impairment, and emotional disturbance—she never mentioned that her father and three brothers had all died with this disease. Perhaps that missing family history was why I became a historian. I wanted to understand my mother's shame, and the origins of her devastating silence. Full-Text PDF Uncovering the true prevalence of Huntington's diseaseLegislation exists to ensure that research into drug development for rare diseases is encouraged. But how sure can we be that a rare disease is, in fact, rare, and what happens when the real prevalence is found to be higher, or lower, than official estimates suggest? Laura Spinney reports. Full-Text PDF

Registries and Selection Bias

Outcomes researchers share a strong interest in determining what is being achieved in practice. In the quest to reveal what is actually being done in medicine, we are often in a position to use existing data about clinical practice and patient experience to answer relevant questions, rather than having to generate data de novo. Patient registries, with their size, scope, and focus on patients who represent those seen in clinical practice, have become an increasingly common source of data for outcomes researchers. There is much to like about patient registries. These organized collections of data about clinical practice are a vehicle by which we can assemble massive amounts of information about patients and use it to assess quality of care, identify patterns of care, facilitate real-world research, and improve performance. In cardiovascular medicine, registries capture information about patients with acute coronary syndromes and heart failure as well as those who undergo procedures related to cardiac catheterization, percutaneous coronary intervention, carotid stents, and internal cardioverter defibrillators. Federal agencies are turning to registries to provide information about quality and produce insights about how to best practice medicine through an emphasis on comparative effectiveness research. Outcomes research articles based on registry data are numerous, including those from NRMI, CRUSADE, GWTG-HF, …

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.

MSJAMA: Orphan diseases and adoptive initiatives.

MARKET-DRIVEN RESEARCH AND DEVELOPMENT HAS OFFERED few new treatments for patients with rare illnesses. In the United States, rare or “orphan” diseases are defined as illnesses with a prevalence of fewer than 200000 individuals at any given time; examples include Creutzfeldt-Jakob disease, Wilson disease, and Landau-Kleffner syndrome. Similarly, “orphan” drugs are those that are likely to be unprofitable either because the patient population is too small or because the disease is prevalent only in developing nations. Thus, even drugs targeting Chagas disease, which threatens a quarter of the population of Latin America, or African trypanosomiasis, which affects nearly 300000 individuals per year, are considered orphan because of their low profitability. The Global Forum for Health Research has estimated that about 90% of total biomedical research funding is spent on only 10% of the world’s health burden. Orphan drug development is limited, in part, by a general lack of knowledge about the pathophysiology of these diseases and the relative unavailability of subjects for clinical trials. The major hurdle, however, is the cost of investing in a pharmaceutical agent with poor market potential. Given the small number of patients who would benefit from an orphan drug, or, in the case of developing nations, the small number of patients who could pay for the medication, there is little motivation for industry to invest in these drugs. Some proponents of orphan drug development have argued for more public funding and legislation to increase market-driven research on orphan drugs. For orphan drug investigation in the United States, these options appear to have been partly successful. The US Orphan Drug Act, signed into law in 1983, provides incentives to the pharmaceutical industry for rare disease drug development such as market exclusivity for orphan drugs designated by the US Food and Drug Administration (FDA), research tax credits for clinical studies of orphan diseases, and the establishment of federal Orphan Product Development grants. Before 1983, only 7 drugs were available to treat orphan diseases. Since then, however, more than 900 orphan drugs have been developed, and more than 200 have received marketing approval by the FDA. In addition, on November 7, 2002, the Rare Diseases Act and Rare Disease Orphan Product Development Act were signed into law. These acts established an Office of Rare Diseases within the National Institutes of Health and authorized appropriations for Rare Disease Regional Centers of Excellence. Japan, Australia, and the European Union have spurred development of drugs for rare diseases in similar ways. These approaches are not nearly as applicable, however, to rare or prevalent diseases of developing nations, which are unable to offer the same market incentives as developed countries. One way to increase funding for orphan drugs in developing nations is through public-private partnerships, whereby the private sector (including for-profit pharmaceutical agencies and not-for-profit philanthropic foundations) joins the public sector (government and universities) to coordinate and fund research projects that address orphan diseases in developing nations. Such partnerships are unique in that they foster competitive drug development but are managed as not-for-profit “social ventures.” Recently established partnerships include the Medicines for Malaria Venture and the Hookworm Vaccine Initiative. While public-private partnerships represent a new mechanism for drug development in developing nations, they do not provide the solution for all orphan illnesses. Diseases that are both rare and endemic to impoverished nations will require largely need-driven, nonprofit approaches. One such initiative, the Drugs for Neglected Diseases initiative (DNDi), was established in 1999 by the nonprofit organization Doctors Without Borders. Although DNDi relies on pharmaceutical companies for scientific expertise and catalogs of active compounds, it operates from the premise that drugs for neglected diseases are public goods. The initiative aims to secure long-term funding from governments, international organizations, foundations, and individual charitable contributions. By forming research initiatives using collaborations between international scientists, health care workers, and nonprofit organizations and by using funds largely from the public sector, DNDi may represent another strategy to address orphan illnesses with low prevalence in developing nations.