Drugs for Rare Diseases: Evolving Trends in Regulatory and Health Technology Assessment Perspectives [Environmental Scan, Issue 42]

Drugs for Rare Diseases: Evolving Trends in Regulatory and Health Technology Assessment Perspectives Issue 42 October 2013 This Environmental Scan is not intended to provide a comprehensive review of the topic. Results are based on selected published literature, grey literature, and other publicly accessible information from various HTA agency and drug regulators’ websites. This report is based on information gathered as of August 2013. Background including a disease affecting fewer than 50,000 people in Japan.3,4 Drugs for rare diseases (DRDs), also referred to as Australia’s Therapeutic Goods Administration, orphan drugs in some jurisdictions, are typically for purposes of orphan drug designation, states small-molecule drugs or biopharmaceuticals that a rare disease is one with a prevalence of (referred to collectively herein as “drugs”) used to fewer than 2,000 people (in a total population treat rare diseases. Due to a shift in the focus of the of 18 million, approximately 1 in 10,000).5 biopharmaceutical industry’s research and In South Korea (Ministry of Food and Drug development priority from blockbuster to niche Safety), rare diseases are defined as diseases drugs, the DRD pipeline and the number of marketed affecting fewer than 20,000 people.6 DRDs are expanding. Taiwan’s Department of Health classifies a rare disease as one that is prevalent in fewer than The purpose of this Environmental Scan is to provide 1 in 10,000 people of the population, difficult to an overview of the DRD landscape and their diagnose and treat, with a genetic origin.6 implications both globally and in Canada. This For Alberta’s publicly funded drug plan, a rare information may assist drug policy decision-makers, disease is defined as a genetic lysosomal storage as well as stakeholders, in understanding the disorder that occurs at a rate of fewer than landscape of DRDs and key issues related to the 1 per 50,000 Canadians, as determined by review and reimbursement of DRDs. Alberta Health.7 Ontario’s publicly funded drug plan’s working Definitions for rare diseases differ based on various definition of rare disease includes those with an jurisdictions’ related legislation or policies, and thus, incidence rate of fewer than 1 in 150,000 live there is no single definition for rare diseases that is births or new diagnoses per year.8 accepted worldwide. These definitions typically include a criterion of disease incidence or Generally, rare diseases are considered to be severe, prevalence. For example (see also summary Table 1): progressive, degenerative, life-threatening, or For purposes of orphan drug designation, the chronically debilitating, with a low prevalence.9,10 United States (US) Food and Drug A large proportion (50%) of rare diseases have their Administration (FDA) considers a rare disease to onset in childhood.11 The majority (80%) of rare be one that affects fewer than 200,000 diseases are genetic in origin, affecting between 3% 1 Americans. and 4% of births,9,12 or have a genetic component.10 Orphan drug designation by the European Allergic, infectious (bacterial or viral), degenerative, Medicines Agency (EMA) uses a condition proliferative and environmental (e.g., chemicals, prevalence in the European Union (EU) of not radiation), or combinations of genetic and greater than 5 in 10,000 people affected environmental causes have been recognized as well, 2 (i.e., 1 in 2,000). yet in other cases specific causes remain In Japan (Ministry of Health, Labour, and unknown.10,12-14 A large percentage of rare diseases Welfare), granting of orphan drug status is undergoing active research are cancers13; however, considered for drugs meeting specific criteria, DRDs encompass all therapeutic areas.11 Drugs for Rare Diseases: Evolving Trends in Regulatory 1 and Health Technology Assessment Perspectives Environmental Scan Table 1: Rare Disease Definitions Organization Rare Disease Definition US FDA Affects < 200,000 Americansa EMA Prevalence in EU not more than 5 in 10,000 (i.e., 1:2,000) Japan’s Ministry of Health, Labour, and Welfare (MHLW) Affects < 50,000 people in Japan Australia’s TGA Prevalence < 2,000 people South Korea’s Ministry of Food and Drug Safety (MFDS), Affects < 20,000 people formerly known as the Korea Food & Drug Administration (KFDA) Taiwan’s Department of Health (DOH) Prevalent in < 1:10,000 population, with a genetic origin and difficult to diagnose and treat Alberta Human Services Genetic lysosomal storage disorders occurring at a rate of < 1:50,000 Canadians (as determined by Alberta Health) Ontario Public Drug Programs (OPDP) An annual incidence rate of < 1:150,000 live births or new diagnoses per year DOH = Department of Health; EMA = European Medicines Agency; EU = European Union; FDA = Food and Drug Administration; MFDS = Ministry of Food and Drug Safety; MHLW = Ministry of Health, Labour, and Welfare; OPDP = Ontario Public Drug Programs; TGA = Therapeutic Goods Administration; US = United States. aThis definition has been in use since the inception of the Orphan Drug Act in 1983. Although each rare disease on its own may affect “Above and beyond worrying about expensive only a small number of individuals, it is estimated therapies, patients diagnosed with a rare disease are that there are between 6,000 and 8,000 distinct rare often surprised to learn that there is limited diseases worldwide,15 with almost weekly reporting scientific knowledge about the causes and natural of newly identified disorders,14 and approximately history of their condition and little or no ongoing 250 new diseases identified annually.6 Prevalence of research.”22 rare diseases can vary among the populations of different countries.13 According to the Canadian With or without available treatments, patients face Organization for Rare Diseases (CORD),16 rare significant challenges in obtaining appropriate care diseases affect 1 in 12 or approximately 2.8 million due to factors such as a lack of physician knowledge Canadians. Thus, there is a “paradox of rarity”9 in about rare diseases or symptoms of a rare disease that although individually the diseases are rare, a being masked by or confused with other conditions, significant portion of a country’s population can be both of which can lead to significant delays in affected. In addition, others may be at risk for or arriving at an accurate diagnosis.23 According to have a rare disease; however, they remain unaware patients with rare diseases surveyed for a recent or undiagnosed.17 Thus, collectively, rare diseases report20, it takes US patients an average of 7.6 years represent a substantial health burden both and United Kingdom (UK) patients an average of nationally in Canada, as well as worldwide, with an 5.6 years to receive an accurate diagnosis, typically estimated 350 million people affected globally.18 involving as many as eight physicians (four primary care and four specialists). In addition, two to three Given the nature of rare diseases, they can misdiagnoses are typical before arriving at a final significantly affect a patient’s autonomy and quality diagnosis. Once patients are correctly diagnosed, of life.19,20 For the majority of these diseases, there they often face inequities and challenges in are currently no specific treatments available to cure accessing any existing approved, and typically costly, or modify the disease,10 as compared with more treatments. Thus patients, their families, and/or common diseases or conditions like diabetes or caregivers can be heavily burdened both financially hypertension. Furthermore, drug therapies that have and emotionally as they seek accurate diagnosis, been developed for rare diseases are typically information, support, and treatments for these rare expensive, with a number of drugs having an conditions. average per patient annual cost that exceeds US$350,000 (in 2010 dollars).21 (See Appendix 1.) Drugs for Rare Diseases: Evolving Trends in Regulatory 2 and Health Technology Assessment Perspectives Environmental Scan Objectives billions per drug,24-26 to the small number of patients suffering from a specific rare disease. Expected Grouped under three subtopics, this Environmental product sales would be inadequate to cover the Scan will address the following questions: costs of bringing the drug to the market, making such development financially unviable for industry.27 A. DRD Regulatory Trends for Key Regulators (US FDA, EMA, Health Canada) However, during the past 30 years, research, 1) What has been the trend for orphan drug development, and availability of innovative drugs to designation and approvals in the US since treat rare diseases have been enhanced through the the institution of the 1983 US FDA Orphan introduction of orphan drug legislation and Drug Act? associated orphan drug policy economic incentives.28 2) What has been the trend for orphan drug Since the first orphan drug legislation was designation and approvals by the EMA since introduced in 1983 in the US (the Orphan Drug Act), the Orphan Regulation came into force in other countries, including Singapore (1991), Japan 2000? (1993), Australia (1997), the EU (1999), Taiwan 3) What is the status of an orphan drug (2000), and South Korea (2003), have also enacted regulatory framework in Canada? regulatory frameworks for developing orphan drugs.6,22,29 Examples of incentives for industry to B. Biopharmaceutical Industry Pipeline for DRD research and develop drugs to treat rare diseases 1) How is the DRD pipeline evolving? vary per country and include research protocol 2) What is the current and predicted market assistance, tax incentives, expedited regulatory volume of DRDs, and their financial effect? reviews, reducing or waiving drug application fees, tax credits, and defined periods of market C. Health Technology Assessment Reimbursement exclusivity.22,30,31 (See also Appendix 2.) Frameworks for DRD 1) How are health technology assessment Orphan Drug Designation and Approval (HTA) and reimbursement perspectives Trends in the US evolving in the DRD evaluation area? (i.e., The US Orphan Drug Act (1983) has been highly are DRD-specific evaluation frameworks successful in incentivizing the development of used, and is cost-effectiveness a mandatory 32 orphan drugs.

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