Rare Disease Research

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Rare Disease Overview

The precise definition of a rare disease is a matter of some debate between nations, but a prevalence of 40 cases per 100,000 or less is the global average. Orphan diseases are disorders that do not yet have a treatment, often (though not always) simply because their rarity makes it economically unviable to do the necessary research; a drug developed for an orphan disease despite the potential loss is known as an orphan drug. As so few rare diseases have viable, tested treatments as yet, most grouping schemes focus on the body system affected by the disease.

Note that due to the nature of this request, the necessity of referencing government and academic resources which have long publication cycles and which are often slow to update, we have not restricted ourselves to sources published in the last two years per our standard procedure. In all cases in which an older source is cited, we have used sources like Google's Scholar database to check for more recent research.

Recognized Definitions

Rare Diseases
  • The US Centers for Disease Control (CDC) defines a rare disease as a condition that affects fewer than 200,000 people worldwide.
  • However, this is not a universal definition. Most regions and countries define rare diseases by prevalence rather than total incidence, ranging from 5 to 76 cases per 100,000, with a global average of 40 cases per 100,000.
  • Qualifiers for a rare disease other than prevalence are rare (<30%) in formal definitions among health organizations worldwide; where they do exist, qualifiers most often relate to the severity of the disease and/or the lack of existing treatments.
    • For example, RareDiseaseDay.org describes rare diseases as, "Quintessentially disabling, the patient's quality of life is affected by the lack or loss of autonomy due to the chronic, progressive, degenerative, and frequently life-threatening aspects of the disease."
  • While "rare disease" is the most common term used internationally, other terms include rare condition, rare disorder, rare and neglected disease (overlapping with orphan disease), very rare disease, syndrome without a name, etc.
  • The lack of a universal terminology or definition has been noted by organizations like the ISPOR Rare Disease Special Interest Group, sparking an international effort to develop a unified standard; thus far, the Group has focused on understanding how different regions and nations define rare disease and has not yet provided recommendations for a global standard.

Orphan Diseases
  • While not formally defined by the CDC, an orphan disease is one that the pharmaceutical industry has not researched or developed a treatment for "because it provides little financial incentive for the private sector to make and market new medications."
    • This is despite the Orphan Drug Act of 1983 attempting to provide additional incentive by offering a seven-year exclusive market to companies who develop drugs to treat rare diseases.
  • As of 2018, about 95% of the 7,000 known rare diseases still lack any treatment options.
  • While an orphan disease may be a rare disease, it can also be a more common disease, such as cholera, malaria, tuberculosis, or typhoid, which has been ignored due to being far more prevalent in the developing world than in developed countries.


Demographic Impact

Useful Charts

  • Useful charts and graphs for this report (including the other briefs in this series) can be found here, with source citations at the bottom of each slide.
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Rare Disease Statistics

Due to disagreement between nations on the definition of a rare disease, pinning down the true prevalence of rare diseases by region has not yet been undertaken by any authoritative source. However, there has been considerable research into the economic and social impact of rare diseases, albeit almost entirely in the Western world. Below that, we have included some of the most powerful facts which might encourage a person to contribute to the research on rare diseases, some of which came from other briefs in this project.

In addition, due to the highly technical nature of this report, we have used an unusual number of extended direct quotes rather than risk misinterpretation and misrepresentation of the information.

Rare Diseases by Region

Social and Economic Costs of Rare Diseases

Note: In this context, an "orphan drug" refers to a drug treatment designed for a rare disease previously considered an orphan disease (see definitions in the overview brief).

  • Worldwide, orphan drug sales are expected to grow at a CAGR of 12.3% over the next five years and reach $242 billion by 2024. Working backward, that gives us a worldwide drug cost of $136 billion in 2019.
  • In the US, orphan drugs for rare diseases comprise 9.6% of the US total drug spend of $451 billion (in 2017), or about $43.3 billion.
  • The NHS estimates that the 10-year cost for an undiagnosed patient with a rare disease averages $16,497 (£13,064), compared to $7,452 (£5,901) for non-rare diseases resulting in a hospital visit.
    • Rare disease patients at least 10 years of age cost the NHS an average of $11,763 (£9,327) compared to $2,825 (£2,240) for others in the same age range.
    • Despite the UK's National Health Service covering more costs than US private insurers, 31% of families affected by rare diseases report having to tap into savings to pay for medical expenses.
  • However, the full social and economic impact, including lost productivity by both patients and family, is not fully known, with even the CDC simply stating, "The economic impact of rare diseases is substantial not only for affected patients and their families, but for society as a whole."
  • However, a few estimates of productivity losses from 2020-2029 due to rare blood diseases are telling:
  • 50% of those diagnosed with a rare disease will eventually require care as adults. Additionally (quoting verbatim):
    • 80% of patients and carers had difficulty completing daily tasks
    • 70% found organizing care time-consuming (with 60% finding it hard to manage)
    • 67% felt that health, social, and local services communicated poorly with each other
  • The financial strain is particularly felt by rare disease patient caregivers:
    • Half (51%) rare disease caregivers experience "high levels of financial strain", and 75% worry about being able to pay for caregiving expenses.
    • Most (86%) of caregivers have faced "financial hardships" owing to their caregiving.
    • Due to this financial strain, caregivers curb household spending (81%), are unable to make long-term financial savings (62%), and use up personal savings (59%), with 9% forced to file for bankruptcy.
  • A 2013 survey of patients and their families in the US and UK (which is still quoted as current in 2019), found significant emotional impact on both patients and their caregivers, with substantial majorities (two-thirds or more) reporting depression, anxiety, isolation from friends and family, and worry caused by a lack of information and certainty about the future. (See slides 7 and 8 of the project slideshow.)
  • Health-related quality of life is about half (44% US / 50% UK) as good for patients with rare diseases compared to the general population, and even lower (58% / 60%) where no treatment is available.
  • As a result of the challenges involved in researching rare diseases (see our other brief in this series), it takes an average of 7.6 years for a US patient and 5.6 years for a UK patient with a rare disease to even receive a proper diagnosis, requiring visits to an average of four different primary care doctors and four specialists.

Key Supporting Facts

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Rare Disease Challenges

Below is an overview of the challenges that face the healthcare industry in diagnosing and treating rare diseases. Note that due to the nature of this request, the necessity of referencing government and academic resources which have long publication cycles and which are often slow to update, we have not restricted ourselves to sources published in the last two years per our standard procedure. In all cases in which an older source is cited, we have used sources like Google's Scholar database to check for more recent information.

In addition, due to the highly technical nature of this report, we have used an unusual number of extended direct quotes rather than risk misinterpretation and misrepresentation of the information.

Key Challenges of Rare and Orphaned Diseases

According to a recent (2018) report by ISPOR's Rare Disease Special Interest Group, the following are the key challenges involved in the research, diagnosis, and treatment of rare and orphan diseases:

  • Due to their rarity, healthcare professionals often lack the awareness and knowledge of rare diseases, greatly increasing the likelihood of misdiagnosis and/or delayed accurate diagnosis.
  • Evaluation of a treatment's effect can be similarly affected:
    • Treatment effects can vary significantly even if the rare disease is properly identified, and the rarity of the disease makes it more difficult to find sufficient sample sizes to overcome a given disease's heterogeneity.
    • The aforementioned geographic variations can limit the ability to recruit patients into clinical trials for new treatments. For example, one German company notes that its diagnostic portfolio of 3,500 rare diseases is 95% European and American data.
    • Consequently, as noted by RareDiseaseDay.org, "research needs to be international to ensure that experts, researchers, and clinicians are connected, that clinical trials are multinational and that patients can benefit from the pooling of resources across borders."
    • Additionally, rare diseases often lack standardized identification codes which makes identifying individuals with a given disease and recruiting them difficult — out of 6,954 rare diseases identified by Orphanet, for example, only 355 had a unique and specific ICD-10 code in 2015.
    • Clinical trials may suffer from selection bias due to favoring the inclusion of patients with a more severe form or presentment of the disease.
  • Even when a rare disease is properly diagnosed and treatment is available, different criteria among different government and non-government healthcare entities can prevent delivery of the treatment.
    • For example, in 2013 the European Medicines Agency noted that several new medicines that they had authorized were not being reimbursed by national health systems due to not meeting the requirements of local health technology assessment (HTA) bodies.
    • As noted in the ISPOR report, "Standard HTA methods require robust information on comparable efficacy, effectiveness, and associated costs of new health care interventions, including data on morbidity, mortality, quality of life (QoL), and health care utilization. Owing to the challenges of research in RDs [rare diseases] and their treatments, not all these types of data may be available at the time of the HTA."
    • This is compounded by the tendency of HTAs to compare new treatments to existing standards of care; in a rare disease, there is often nothing to compare a new treatment to.
    • Likewise, a lack of "robust long-term outcomes data" on the normal trajectory of a disease can impede the ability to evaluate a treatment's efficacy.
    • White HTA agencies are beginning to develop processes tailored to the evaluation of rare disease treatments, there are still many hurdles: "Budget constraints, paired with the uncertainties related to effectiveness, value-for-money, and budget impact of RD technologies, increase HTA authorities’ hesitancy in issuing positive reimbursement decisions."

The above challenges are echoed in other sources, including the CDC.

Other Challenges

Key Players and Research Funding Sources

Our research did not discover an authoritative list of key players, likely due to the nature of this sector (i.e., we could not use market report abstracts to determine key players as we might for a profitable industry sector). Consequently, we have determined key players primarily through finding reference to them in diverse sources as a means of gauging their impact.

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Rare Disease Key Players (1)

Below is an overview of two key governmental players in the rare disease sector of the healthcare industry, the Rare Diseases Clinical Research Network (RDCRN) and FDA Office of Orphan Products Development (OOPD).

Rare Diseases Clinical Research Network (RDCRN)

  • The Rare Diseases Clinical Research Network (RDCRN), established in 2003 by the NIH Office of Rare Diseases, consists of 20 separate clinical research consortia and brings together physician-scientists and other researchers to find cures for rare diseases.
  • RDCRN is organized and funded by "NCATS and 9 other NIH entities," with private patient advocacy groups occasionally providing additional funding. NIH provided an additional $31 million in grants to 20 teams of network researchers in 2019 for the study of "a wide range of rare diseases."
  • The current consortia of the RDCRN include:
    • Brain Vascular Malformation Consortium
    • Brittle Bone Disorders Consortium
    • Congenital and Perinatal Infections Consortium
    • Consortium of Eosinophilic Gastrointestinal Disease Researchers
    • Dystonia Coalition
    • Congenital Disorders of Glycosylation Consortium
    • Genetic Disorders of Mucociliary Clearance Consortium
    • Global Leukodystrophy Initiative Clinical Trials Network
    • Hyperphenylalaninemia Disorders Consortium
    • Inherited Neuropathies Consortium
    • Lysosomal Disease Network
    • Myasthenia Gravis Rare Disease Network (MGNet)
    • Nephrotic Syndrome Network
    • North American Mitochondrial Disease Consortium
    • Porphyrias Consortium
    • Primary Immune Deficiency Treatment Consortium
    • Urea Cycle Disorders Consortium
    • Vasculitis Clinical Research Consortium

FDA Office of Orphan Products Development (OOPD)

  • The mission of the FDA Office of Orphan Products Development (OOPD) is, in their own words, "to advance the evaluation and development of products (drugs, biologics, devices, or medical foods) that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions" by evaluating scientific and clinical data submitted by researchers.
  • OOPD provides incentives through several programs:
  • OOPD also provides grants to researchers to "identify and promote the development of orphan products."
    • While a list of grants is available through a searchable database, the amounts of the grants are not generally publicized.
    • However, the FDA did announce awarding 12 clinical trial research grants totaling over $15 million in late 2019, with 75% of the funds dedicated to studies on children.
    • It also announced two grants totaling over $4.1 million to study the natural history of rare diseases; it is hoped that the information from these studies "can facilitate design of efficient clinical trials to test future treatments."
    • We are uncertain whether the above constitute the entirety of the OOPD's grants for 2020.

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Rare Disease Key Players (2)

Below is an overview of three key private players in the rare disease sector of the healthcare industry, the ISPOR Rare Disease Special Interest Group, International Rare Diseases Research Consortium (IRDiRC), and National Organization for Rare Disorders (NORD).

ISPOR Rare Disease Special Interest Group

  • ISPOR, founded in 1995, is an organization "of dedicated volunteers and visionaries with the goal of serving as a catalyst for advancing the science and practice of health economics and outcomes research worldwide."
  • Its members comprise healthcare stakeholders at all levels, from researchers and academics, government regulators, payors, providers, and patient advocates.
  • The ISPOR Rare Disease Special Interest Group is an international working group, "comprising ISPOR members from the United Kingdom, Germany, Serbia, Belgium, Canada, Italy, The Netherlands, Switzerland, and the United States" in addition to researchers in the APAC and LatAm regions.
  • ISPOR's total assets in 2018 were $17.4 million, up from $16.6 million in 2017. A list of funders is not publicly available.
  • Starting in 2013, the Group established the Rare Disease Terminology & Definitions Used in Outcomes Research Working Group due to the "lack of a universal definition of rare diseases or the technologies used in their treatments and the existing diversity in the use of different definitions used to describe rare diseases and the underlying connotations associated with them."

International Rare Diseases Research Consortium (IRDiRC)

  • International Rare Diseases Research Consortium (IRDiRC) is a global organization that unites healthcare stakeholders (with a similar range to ISPOR) across Africa, Asia, Australia, North America, and Europe.
  • Launched in 2011, IRDiRC was originally conceived to contribute to the development of 200 new therapies and diagnostic methods for rare diseases by 2020; having accomplished that goal three years early, the Consortium set forth three new goals to achieve by 2027 (quoted verbatim):
    • Goal 1: All patients coming to medical attention with a suspected rare disease will be diagnosed within one year if their disorder is known in the medical literature; all currently undiagnosable individuals will enter a globally coordinated diagnostic and research pipeline
    • Goal 2: 1000 new therapies for rare diseases will be approved, the majority of which will focus on diseases without approved options
    • Goal 3: Methodologies will be developed to assess the impact of diagnoses and therapies on rare disease patients
  • The Consortium does not provide direct funding to new rare disease treatments; rather, it has members that contribute funding opportunities for promising research. As of 2017, the Consortium included nearly 50 funding and patient organizations across 20 countries and four continents (a map can be found on slide 4 of the project slideshow). Each invests a minimum of $10 million over 5 years.
  • IRDiRC also provides "Recognized Resources" to "accelerate the pace of translating discoveries into clinical applications," such as platforms, tools, standards & guidelines, and databases.

National Organization for Rare Disorders (NORD)

  • The National Organization for Rare Disorders (NORD) is a 501(c)(3) patient advocacy organization that provides tools, databases, and forums for rare disease researchers.
  • NORD facilitates grants funded by private donors (many of which specify the disease the grant is to be used for) and has funded over $7 million in research since 1989 and $375,000 in 2018 alone. It requires a minimum of $35,000 to fund a grant, though that minimum may be spread across several donors.
  • All told, NORD has $50.1 million in assets.
  • NORD is funded through several revenue streams (quoted verbatim), but does not publish a list of donors:
    • administrative fees and grants for patient assistance programs
    • foundation and corporate grants
    • individual and organizational membership dues
    • an annual gala
    • philanthropic contributions from individuals, organizations, and companies

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Rare Disease - Innovations

Below is a brief overview of four recent innovations in the rare disease diagnosis and treatment realm, including genome sequencing, the Rare Conditions Care Value (RCCV) Program, the creation of the Global Rare Disease Commission, and the recent partnership of Chiesi Farmaceutici with StartUp Health. Due to the highly technical nature of this report, we have used an unusual number of extended direct quotes rather than risk misinterpretation and misrepresentation of the information.

Genome Sequencing

  • Genome sequencing is becoming an increasingly important tool for diagnosing patients with rare diseases both in the US and overseas.
  • As noted by the CDC, "Molecular genomic diagnosis of rare diseases can lead to changes in medical care including use of existing medications or development of new ones to help people with specific mutations, as well as discontinuing ineffective therapies."
  • Presently, diagnostic success rates range from 25-50%.
  • Screening newborns for rare genetic conditions and other metabolic disorders has become more commonplace, with screening for over 30 disorders now recommended by the Advisory Committee on Heritable Disorders in Newborns and Children.

The Rare Conditions Care Value (RCCV) Program

  • Express Scripts, in conjunction with PinnacleCare, announced the launch of a new initiative, the Rare Conditions Care Value (RCCV) program, in June 2018. It focuses on rare diseases, like "hemophilia, Huntington disease, Gaucher disease, acromegaly, alpha-1 deficiency, hereditary angioedema, and idiopathic pulmonary fibrosis," which are seeing significant increases in diagnoses and treatments.
  • The RCCV includes the Second Opinion support service, "which offers guidance and expert case review for patients on an individual basis, with PinnacleCare," reducing the financial, physical, and emotional burden on patients and their caregivers.
  • According to Dr. Glen Stettin, SVP of Clinical, Research, and New Solutions at Express Scripts, "Getting to the right diagnosis and the right therapy is critically important for the more than 30 million Americans currently with a rare disease... In order to provide affordable access to these newer therapies, we need to make sure that the diagnosis is correct, and that the pharmaceutical treatment plan is based upon expert best practices."

Global Rare Disease Commission

  • In 2018, EURODIS-Rare Diseases Europe, Microsoft, and Takeda came together to launch the Global Commission to End the Diagnostic Odyssey for Children with a Rare Disease, aka the Global Rare Disease Commission or simply the Global Commission.
    • Note: Due to the newness of the Global Commission and a lack of public information about its funding and reach, we have not included it in our brief on key players.
  • The Global Commission seeks to bring together both healthcare and technology experts "from around the world who have brought their creativity, technological expertise, and passion to accelerate the time to diagnosis."
  • The Commission seeks to overcome the challenges facing proper diagnosis, treatment, and research for rare diseases (detailed in a separate brief) through three main tracks:
  • The Commission particularly seeks to bridge the gaps in knowledge and communication with technology tools, including (quoted verbatim):
    • Multifactorial machine learning to recognize symptom patterns.
    • Collaboration tools for "intelligent triage" and clinical geneticist virtual panel consultation.
    • A blockchain-based patient registry and rare disease passport.

Chiesi Farmaceutici Partners with StartUp Health

  • In 2018, Chiesi Farmaceutici partnered with StartUp Health, "a global health innovation company focused on achieving 'Health Moonshots' ... a series of health themes which are all interconnected with one another." In this case, the Moonshots are focused to a large extent on tackling rare diseases.
  • The deal combines Chiesi's "deep expertise in respiratory care, neonatology, specialty care and rare diseases with StartUp Health’s extensive global network of innovative companies and partners, stimulating research and the availability of therapeutic solutions for all patients."
  • Giacomo Chiesi stated of this partnership, "The number of patients affected by rare diseases doesn’t matter to us. What matters is the patient and increasing disease awareness."
  • The partners put out a global call for innovators and entrepreneurs to join StartUp Health's "expanding portfolio" of experts working in the following areas:
    • Provider engagement, communications, and community building
    • Digital diagnostics
    • Remote monitoring & care coordination
    • Patient-provider communications

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Rare Disease Conferences and Journals

Below is a listing of three conferences and seven peer-reviewed journals (many of which are online and open-access) which focus on rare diseases and orphan drugs. Due to a high degree of overlap, we have quoted the descriptions of the journals at length to best differentiate their emphases and voices.




From Part 07