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

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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.)

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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. In the eight to ten years before its consideration?) enactment, the FDA had approved only ten rare 2) Do any of Canada’s publicly funded drug 33 disease drugs for marketing. According to the US plans use a rare-disease drug-specific FDA Orphan Drug Designations and Approvals evaluation framework to evaluate DRD 34 database on August 6, 2013, since 1983 to the end funding? of 2012 a total of 2,740 orphan drug designations

have been made (note that this figure does not Findings exclude designations that have been withdrawn) and 427 of these designated drugs had received A. DRD Regulatory Trends for marketing approval. Based on these figures, Key Regulators (US FDA, EMA, approximately 15.5% of US orphan drug designations Health Canada) have been approved. It is noteworthy that the US FDA definition of a DRD has not been adjusted for US Under normal drug marketing conditions, the population growth since 1983. Figure 1 summarizes pharmaceutical industry historically lacked incentive the number of orphan drug designations and unique to commit the high costs associated with developing orphan drug approvals from 1984 to 2011. a new drug, estimated to be in the millions or

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Figure 1: Orphan Drug Designations and Unique Orphan Drug Approvals 1984 to 201135

From an average of 63 designations per year in the Orphan Drug Designation and Approval 1990s, the number of US orphan drug designations Trends in the EU has doubled to an average of 126 designations per In the year 2000, EU orphan drug legislation, the year between 2001 and 2010, reflecting increased Regulation on Orphan Medicinal Products biopharmaceutical industry interest in developing (Regulation (EC) No 141/2000 of December 16, drugs to treat rare diseases. At an average of 10 1999), came into force. As with the US Orphan Drug approvals per year, the number of orphan drug Act, its intention was to offer incentives to industry approvals between 1984 and 2010 has remained for developing and marketing drugs to diagnose, relatively constant; however, as the total number of treat, or prevent rare conditions.37 US drug approvals has been declining since the peak in the 1990s, the proportion of new drug approvals The number of orphan drug designations granted by attributed to orphan drugs has risen from 17% in the the European Commission for the EU has increased 1990s to over 35% between 2008 and 2010, a trend steadily over the first 12 years of the orphan drug that is expected to continue.36 program. From 14 designations granted in the initial

year to a total of 148 granted designations in 2012, a Figure 2 provides a breakdown of US orphan drug total of almost 1,100 designations (not excluding approvals by therapeutic area from 2006 to 2011. expiries or withdrawals) have been granted from The majority of approvals (33%) were for oncology 2000 to 2012 inclusive.38 These orphan drug products; the next largest therapeutic categories, designations correspond to a total of 79 individual accounting for 17% of approvals each, were drugs that have received centralized marketing gastrointestinal disorders and inborn errors of authorization for the EU from 2000 to 2012, metabolism, and neurological conditions. representing approximately 7% of all orphan drug Immunological diseases and rheumatology disorders designations.38 (See Figure 3) Note that, following each represented 8% of approvals for this time EMA central authorizations, individual EU member period. The remaining 17% of approvals were other states are responsible for the funding of orphan therapeutic areas, each representing less than 5%.36 drugs in their various jurisdictions.

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Figure 2: US Orphan Drug Approvals by Therapeutic Area (2006 to 2011)39

GI, inborn errors of metabolism 17% Oncology 33% Neurology 17% Rheumatology 8% Hematology 8% Other 17%

Figure 3: EU Orphan Drug Designations Granted and Approved; Individual Drugs Approved for Marketing (2000 to 2012)

160 Number of Orphan Drug Designations Granted 140 (for individual indications) BAR ON LEFT 120

100 Number of Orphan Drug Designations Approved for Marketing 80 MIDDLE BAR

60 Number of Individual Drugs 40 Approved for Marketing (a single drug may have multiple 20 approved designations for different indications) BAR ON RIGHT 0

(Figure 3 based on data retrieved from European Commission Register of Designated Orphan Medicinal Products on April 16, 201338)

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For the years 2000 to 2011, Figure 4 below illustrates therapeutic area for positive orphan drug the distribution by various therapeutic areas for designation opinions from COMP was oncology which the EMA’s Committee on Orphan Medicinal (41%), followed in decreasing order by Products (COMP) provided positive orphan drug musculoskeletal and nervous system (12%) and also designation opinions to the European Commission metabolism (12%), cardiovascular and respiratory (EC) for approval (as opposed to orphan drug (8%), immunological (7%), anti-infectious (4%), and designations granted by the EC; however, the hematology drugs (3%). Therapeutic categories majority of positive opinions from COMP are individually representing less than 3% of the total typically adopted by the EC). The most common are captured under the category “other” (13%).37

Figure 4: EU Orphan Drug Designations by COMP by Therapeutic Area (2000 to 2011)37

Source: Aymé S., and Rodwell C., eds., “2012 Report on the State of the Art of Rare Disease Activities in Europe of the European Union Committee of Experts on Rare Diseases,” July 2012.

Proposed Orphan Drug Regulatory Framework compromising their safety. The document outlines for Canada an internationally aligned orphan drug regulatory scheme that aims to provide transparency in Until recently, Canada has had no established gathering and sharing orphan drug information with policies or legislative framework specifically for rare all stakeholders (including patients, health care disease drug development and approval. On professionals, researchers, and payers), as well as October 3, 2012, the federal government international regulatory partners.42 announced the development of an orphan drug framework for Canada.40 This legislative framework The Health Canada draft discussion document for would be life-cycle-based, encompassing the the orphan drug regulatory framework42 proposes designation, authorization, and post-market defining an orphan drug as one that meets a number monitoring of orphan drugs, as well as incentivizing of criteria as follows: related innovative research in Canada.41  a drug “intended for the diagnosis, treatment,

mitigation or prevention of a life-threatening, Health Canada has since developed a draft seriously debilitating, or serious and chronic discussion document proposing a comprehensive disease or condition affecting not more than five orphan drug framework with a goal of providing in ten thousand persons in Canada, and Canadians with access to orphan drugs without

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 the drug is not currently authorized by the  granting of orphan drug designations to multiple Minister or if currently authorized, it will provide sponsors submitting applications for the same a potentially substantial benefit for the patient drug indicated for the same rare disease distinguishable from the existing therapy.”42  granting of multiple orphan drug designations for different rare diseases to a single drug. In keeping with orphan drug regulatory frameworks in other countries, sponsors would be asked to Due to the large number of identified rare diseases, submit applications for orphan drug designation to Health Canada recognizes that it will not always have Health Canada. Those meeting the application the necessary in-house scientific and medical requirements, which include Health Canada’s expertise to evaluate all DRD regulatory submissions. definition of an orphan drug, would qualify for the Therefore, when necessary, the framework indicates formal granting of an orphan drug designation. In that Health Canada will seek advice from external addition, Health Canada also proposes that it would experts to assist in making the best possible recognize orphan drug designations made by other regulatory decisions for these drugs. In addition, recognized international regulatory agencies (e.g., patient input will be sought in order to provide the US FDA, EU EMA). insight into disease severity and level of unmet medical need for a particular rare disease, to be A Health Canada orphan drug designation would taken into consideration in the regulatory approval subsequently provide drug sponsors access to a process. number of proposed regulatory incentives, including:  scientific and clinical trial protocol advice by Before this proposed formal orphan drug regulatory Health Canada or in-common with international framework, Health Canada had already approved a regulators number of drugs indicated for rare diseases.  priority review of the drug submission However, equitable access to these expensive drugs  regulatory fee reductions (for small to medium through provincial and territorial publicly funded enterprises) drug plans remains an issue for Canadian patients.  linkage with the existing eight-year market exclusivity post approval (plus an additional six B. Biopharmaceutical Industry Pipeline months for drugs with qualifying pediatric study for DRD results). 1) DRD Pipeline In order to promote orphan drug research, Table 2 provides a snapshot of some identified DRDs innovation, and increased potential for drugs to in phase II or III of development, or DRDs approved successfully reach the market, Health Canada’s in the US or EU but not in Canada, based on proposed orphan drug regulatory framework would information from drug pipeline reports.43-45 be aligned with other jurisdictions in that it would The DRD pipeline is rapidly evolving, and grows allow: almost daily.

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Table 2: Snapshot of DRD Pipeline Nonproprietary Company Disease or Condition Phase of Comments Name/Code Name Development (Brand Name) Autoimmune Disorders Amifampridine BioMarin Lambert-Eaton ECa approved EMA orphan drug designation (Firdapse in EU) myasthenic syndrome 23/12/2009 18/12/2002 Canakinumab Novartis Systemic juvenile FDA approved (Ilaris) idiopathic arthritis 29/05/2013 (SJIA) Golimumab Janssen Sarcoidosis Phase II FDA orphan drug designation (Simponi Aria) Biologics 21/05/2012 (formerly Centocor) Human gamma Latona Life Juvenile rheumatoid Phase II FDA orphan drug designation globulin Sciences arthritis completed 25/05/2001 (Oralgam) Human mesenchymal Osiris Treatment of type 1 Phase II FDA orphan drug designation stem cell therapy Therapeutics diabetes with residual 30/04/2010 (Prochymal) beta cell function Infliximab Janssen Chronic sarcoidosis Phase III FDA orphan drug designation (Remicade) Biologics 21/05/2003 (formerly Centocor) Rintatolimod Hemispherx ME/CFS Complete (Ampligen) (also Phase II response letter completed for from FDA treatment of AIDS) 04/02/2013 Cancer Algenpantucel-L NewLink Pancreatic cancer Phase III FDA orphan drug designation (HyperActure Genetics 21/10/2010 Pancreas) Astuprotimut-R GlaxoSmithKline MAGE-A3 positive Phase III (Zumagev) non-small-cell lung cancer

Mage-A3 positive stages IIb to IV Phase III malignant melanoma Bevacizumab Genentech Ovarian cancer Phase III FDA orphan drug designation (Avastin) 09/02/2006 Stomach cancer Phase III FDA orphan drug designation 20/11/2009 Fallopian tube cancer Phase III Cabozantinib Exelixis Follicular medullary FDA approved FDA orphan drug designation (Cometriq) and anaplastic thyroid 29/11/2012 29/11/2010 carcinoma and metastatic or locally advanced papillary thyroid cancer Calaspargase pegol Sigma-Tau Acute lymphoblastic FDA BLA (aka EZN-2285) leukemia preparation

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Table 2: Snapshot of DRD Pipeline Nonproprietary Company Disease or Condition Phase of Comments Name/Code Name Development (Brand Name) Carfilzomib Onyx Multiple myeloma FDA approved FDA orphan drug designation (Kyprolis) Therapeutics 20/07/2012 18/01/2008 EMA orphan drug designation 03/06/2008 Dabrafenib GlaxoSmithKline BRAF V600 mutation FDA approved FDA orphan drug designation (Tafinlar) positive stage IIB 05/29/2013 12/01/2011 through IV melanoma ECa approved 26/08/2013 Decitabine (Dacogen) Eisai Acute myeloid FDA complete FDA orphan drug designation leukemia response letter 04/08/2006 07/05/2012, EMA approved 20/09/2012 Denosumab Amgen Giant cell tumour of FDA approved FDA orphan drug designation (Xgeva) bone 13/06/2013 20/12/2010 EGEN-001 EGEN Ovarian cancer Phase II Gene therapy (monotherapy) Elacytarabine Clavis Pharma Acute myeloid Phase III leukemia Everolimus Novartis Hepatocellular Phase III Anticipated FDA filing 2013 (Afinitor) carcinoma Histamine EpiCept Acute myeloid ECa approved FDA orphan drug designation dihydrochloride leukemia 07/10/2008 15/12/1999 (Ceplene) EMA orphan drug designation 11/04/2005 Lenalidomide Celgene Mantle cell lymphoma FDA approved FDA orphan drug designation (Revlimid) 05/06/2013 27/04/2009 Midostaurin Novartis Acute myeloid Phase III Anticipated regulatory filing in (aka PKC412) leukemia 2015; for patients who carry a mutated version of the gene encoding FLT3 Paclitaxel, protein Celgene Stage IIb to IV Phase III FDA orphan drug designation (albumin) bound) melanoma 1/10/2009 (Abraxane) Pancreatic cancer Phase III FDA orphan drug designation 03/09/2009 Paclitaxel poliglumex Cell Glioblastoma Phase II FDA orphan drug designation (Opaxio) Therapeutics- multiforme 20/09/2012 tics Inc. Pomalidomide Celgene Multiple myeloma FDA approved FDA orphan drug designation (Pomalyst) 08/02/2013 15/01/2003 EMA orphan drug designation 08/10/2009

Pralatrexate (Folotyn) Allos Advanced or EMA – CHMP Therapeutics metastatic transitional negative opinion cell carcinoma of the 19/04/2012 urinary bladder

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Table 2: Snapshot of DRD Pipeline Nonproprietary Company Disease or Condition Phase of Comments Name/Code Name Development (Brand Name) Rindopepimut Celldex Newly diagnosed Phase III EGFR3-expressing (aka CDX-110) Therapeutics glioblastoma glioblastoma multiforme multiforme Trabedersen Antisense High-grade glioma Phase III FDA orphan drug designation (aka AP 12009) Pharma (terminated –lack 05/06/2002 of patients)

Pancreatic cancer Phase II FDA orphan drug designation 21/07/2009; EMA orphan drug Malignant melanoma Phase II designation 24/07/2009 FDA orphan drug designation 05/06/2002 Cardiovascular Diseases Imatinib Novartis PAH FDA new drug FDA postponed Cardiovascular (aka QT1571) application & Renal Drugs Advisory withdrawn Committee meeting for August 2012; Novartis has withdrawn the submission to allow more time to generate information for FDA review Macitentan (Opsumit) Actelion PAH Under review by FDA NDA accepted 14/12/2013 FDA (12 month review anticipated) EMA orphan designation 27/09/2011 Selexipag Actelion PAH Phase III Phase III GRIPHON study results expected mid-2014 (interim analysis for efficacy and futility expected mid-2013) Riociguat Bayer PAH; Under review by 02/11/2013 Bayer announced Persistent/recurrent FDA submitting NDA to US FDA. chronic thromboembolic 04/08/2013 US FDA granted pulmonary priority review for both hypertension (CTEPH) indications Treprostinil diolamine United PAH Rejected twice by First FDA complete response Therapeutics FDA letter October 23, 2012; second on March 25, 2013. United Therapeutics is committed to working collaboratively with FDA to get approval. http://ir.unither.com/releasedet ail.cfm?releaseid=750550 Genetic Disorders Alipogene tiparvovec UniQure Lipoprotein lipase ECa approved First gene therapy approved for (Glybera) deficiency 25/10/2012 use in Europe

Company preparing to file in US, Canada and other markets Amifampridine BioMarin Lambert-Eaton ECa approved EMA orphan drug designation (Firdapse) myasthenic syndrome 23/12/2009 18/12/2002

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Table 2: Snapshot of DRD Pipeline Nonproprietary Company Disease or Condition Phase of Comments Name/Code Name Development (Brand Name) Ataluren PTC Therapeutics Nonsense mutation Phase IIb Dec 2012: EMA validated a (aka PTC124) Inc. Duchenne muscular Marketing Authorization dystrophy Application (MAA) seeking conditional approval for ataluren, based on a positive benefit/risk ratio in the available data which, while not yet comprehensive, indicate that the public health benefits of immediate availability of a medicine outweigh its risks. The approval is renewed on a yearly basis until all obligations have been fulfilled, and is then converted from a conditional approval into a full approval. Conditional approvals can only be granted for medicines that satisfy an unmet medical need. Deferiprone ApoPharma Friedreich ataxia Phase II FDA orphan drug designation (Ferriprox) 31/07/2008 Drisapersen GlaxoSmithKline, Duchenne muscular Phase III June 2013: granted breakthrough (aka Prosensa dystrophy therapy designation by FDA PRO051/GSK2402968) Elosulfase alfa (aka BioMarin Mucopolysaccharidosis Under review by BMN-110) IVA (MPSIVA; aka FDA and EMA Morquio A syndrome) Eteplirsen Sarepta Duchenne muscular Phase II complete April 2013: discussions of dystrophy potential application to FDA for accelerated approval of NDA based on Phase II data

Galsulfase BioMarin Mucopolysaccharidosis FDA approved FDA orphan drug designation (Naglazyme) IV (MPSVI; aka 05/31/2005, ECa 17/02/1999 Maroteaux-Lamy approved EMA orphan drug designation Syndrome) 24/01/2006 14/02/2001 Lenti-D (autologous Bluebird Bio Childhood cerebral Phase II/III planned Gene therapy. Plan to initiate a CD34+ hematopoietic adrenoleukodystrophy Phase 2/3 clinical study called the stem cells transduced (CCALD) ALD-102 Study in CCALD in the US with lentiviral vector and Europe in 2013. Lenti-D encoding the FDA orphan drug designation human ABCD1 cDNA) 19/04/2012 EMA orphan drug designation 06/06/2012 Migalastat Amicus Fabry Disease Phase III FDA orphan drug designation (Amigal) Therapeutics, 25/02/2004; also has EMA GlaxoSmithKline (22/05/2006) and Japan orphan drug designation. Amicus delaying FDA submission until late 2014 or early 2015 with another phase III study required

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Table 2: Snapshot of DRD Pipeline Nonproprietary Company Disease or Condition Phase of Comments Name/Code Name Development (Brand Name) Pegylated recombinant BioMarin Phenylketonuria (PKU) Phase II FDA orphan drug designation phenylalanine 08/03/1995 ammonia lyase (PEG-PAL) Being developed as potential treatment for patients not adequately controlled by Kuvan. PF-06460031 Pfizer, Vaso-occlusive crisis Phase II FDA fast-track status granted (aka GMI-1070) GlycoMimetics associated with sickle cell disease FDA orphan drug designation 17/02/2009 Reslizumab (Cinquil) Cephalon Eosinophilic esophagitis Phase IIb/III FDA orphan drug designation (children) 19/12/2007 Taliglucerase alfa Pfizer Type 1 Gaucher Disease FDA approved EMA’s CHMP recommended (Elelyso) 05/01/2012 against marketing authorization since prior authorization of Shire’s VPRIV (velaglucerase alfa) continues to benefit from orphan market exclusivity in the EU. Tirasemtiv Cytokinetics ALS Phase IIb FDA fast-track status granted (aka CK-2017357) Hematologic Disorders Deferiprone ApoPharma Transfusional iron FDA approved (Ferriprox) overload due to 14/10/2011 thalassemia syndromes ECa approved 25/08/1999 Recombinant Factor VIII Biogen Idec, Hemophilia A Under review by FDA orphan drug designation fusion protein (rFVIIIIFc) Swedish Orphan FDA and TGA Biovitrum (Sobi) Submission to EMA once study in children under 12 years of age is complete Recombinant Factor IX Biogen Idec, Hemophilia B Under review by FDA orphan drug designation fusion protein Swedish Orphan FDA (rFIXFc) Biovitrum (Sobi) Reslizumab Cephalon Hypereosinophilic Phase III (Cinquil) syndrome Ruxolitinib phosphate Incyte Polycythemia vera Phase III Planned FDA filing in 2014 (JAKAFI US; JAKAVI Canada) Neurologic Disorders Amitriptyline/ EpiCept Postherpetic neuralgia Phase II completed FDA orphan drug designation ketamine 19/01/2010 (aka EPICEPT NP-1) (AmiKet)

Arimoclomol CytRx ALS Phase II/III FDA orphan drug designation 29/03/2005

Onabotulinum toxin A Allergan Juvenile cerebral palsy Phase III FDA orphan drug designation (Botox) 06/12/1991

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Table 2: Snapshot of DRD Pipeline Nonproprietary Company Disease or Condition Phase of Comments Name/Code Name Development (Brand Name) Pridopidine Teva (formerly Huntington disease Phase III Advanced-stage clinical studies (aka ACR-16 NeuroSearch) (conducted in US, EU and Canada) (Huntexil) showed significant treatment effect on Total Motor Score [TMS]), but failed to meet the primary endpoint (Modified Total Motor score [mTMS]). Consultation with FDA and EMA in first half of 2012 indicated need for further trial for submission filing. Progesterone BHR Pharma Traumatic brain injury Phase III FDA orphan drug designation (aka BHR-100) 03/09/2009 Tirasemtiv Cytokinetics ALS Phase IIb Phase IIb potential registration (aka CK-2017357) clinical trial (BENEFIT-ALS) results expected early 2014 Clazosentan Actelion Subarachnoid FDA orphan drug designation hemorrhage 16/02/2006 Clobazam Lundbeck Lennox-Gastaut FDA approved FDA orphan drug designation (ONFI) syndrome 21/10/2011 18/12/2007 Dichlorphenamide Taro, University Primary periodic Phase III FDA orphan drug designation (DCP) of Rochester paralyses 02/09/2010 Tasimelteon Vanda Non-24-hour Phase III FDA orphan drug designation Pharmaceuticals sleep/wake disorder 30/04/2010 (in Smith-Magenis syndrome) and 19/01/2010 (in blind individuals without light perception) EMA orphan drug designation 23/02/2011 (in blind individuals without light perception) Tideglusib Noscira Progressive Phase II FDA fast-track status granted in (aka NP-12) supranuclear palsy 2010 (Zentylor) FDA orphan drug designation 13/10/2009 EMA orphan drug designation (November 2009) Other ATL1103 Isis, Antisense Acromegaly Phase II 04/10/2013: ATL1103 Phase II trial Therapeutics for acromegaly – dosing of patients commenced http://www.antisense.com.au/wp- content/uploads/downloads/2013 /04/ASX-13_-April_- ATL1103_Phase-II-trial_dosing- commenced-final.pdf

Aztreonam Gilead Non-cystic fibrosis Phase III Inhalation dosage form (Cayston) bronchiectasis FDA orphan drug designation 15/05/2009

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Table 2: Snapshot of DRD Pipeline Nonproprietary Company Disease or Condition Phase of Comments Name/Code Name Development (Brand Name) Chenodeoxycholic acid Sigma-Tau Cerebrotendi-nous FDA NDA FDA orphan drug designation (Xenbilox) xanthomatosis preparation 12/02/2007 Defibrotide Sigma-Tau, Hepatic venoocclusive FDA NDA Gentium disease treatment after preparation stem cell transplantation Ex vivo cultured adult Osiris Acute graft versus host Phase III Stem cell therapy; human mesenchymal Therapeutics disease FDA orphan drug designation stem cells 14/12/2005 (Prochymal) EXN-2279 (aka Sigma-Tau Adenosine deaminase Phase III polyethylene glycol deficiency recombinant adenosine deaminase [PEG-rADA]) Glycerol Hyperion Urea cycle disorders FDA approved FDA orphan drug designation phenylbutyrate Therapeutics 01/02/2013 27/04/2009 (Ravicti) rAAv1-CB-hAAT Applied Genetic Alpha-1 antitrypsin Phase II Gene therapy; Phase 2b clinical Technologies deficiency trial will begin in 2014 Corp. Teduglutide NPS Short bowel syndrome FDA approved FDA orphan drug designation (Gattex) Pharmaceuticals 21/12/2012 29/06/2000 EMA orphan designation 11/12/2001

Note: The date format throughout table is DD/MM/YYYY. aEC = European Commission (Orphan drugs are authorized in Europe through the centralized procedure, for which market authorization applications are made directly to the EMA, and the granting of market authorizations binding to all of the EU member states are granted by the European Commission). AIDS = acquired immune deficiency syndrome; ALS = amyotrophic lateral sclerosis; BLA = biologic license application; CCALD = childhood cerebral adrenoleukodystrophy; CHMP = Committee for Medicinal Products for Human Use; CFS = chronic fatigue syndrome; CTEPH = persistent/recurrent chronic thromboembolic pulmonary hypertension; EMA = European Medicines Agency; FDA = Food and Drug Administration; ME = myalgic encephalomyelitis; MPSIVA = mucopolysaccharidosis; NDA = new drug application; PAH = pulmonary arterial hypertension; PKU = phenylketonuria; SJIA = systemic juvenile idiopathic arthritis.

2) Current and Predicted DRD Market Volume and  by 2018, global orphan drug sales will grow to Financial Impact $127 billion, and  orphan drugs will represent 15.9% of worldwide Global Orphan Drug Sales prescription sales, excluding generics, by 2018 The worldwide orphan drug market is expected to (as compared with 5.1% in 1998). See Figure 5. grow significantly in the future. A recently released report46 forecasts that:

Drugs for Rare Diseases: Evolving Trends in Regulatory 14 and Health Technology Assessment Perspectives Environmental Scan

Figure 5: Worldwide Orphan Drug Sales and Share of Prescription Drug Market (1998 to 2018)46

Source: From EvaluatePharma. EvaluatePharma Orphan Drug Report 2013 [Internet]. London: Evaluate Ltd.; 2013. [cited 2013 Sep 25]. Available from: http://info.evaluategroup.com/OrphanDrug2013_BSB_LP.html?BSB=TEXT Copyright © 2013 Evaluate Ltd. Reproduced by permission of Evaluate Ltd.

According to the Pharmaceutical Research and Table 3: Number of Drugs for Manufacturers of America (PhRMA),47 the Rare Disease in Development organization that represents US-based Year of PhRMA Report on Number of biopharmaceutical researchers and biotechnology Rare Disease Medicines Medicines in companies, the number of rare disease drugs in in Development Development development has been rising steadily over the years. 1989 133 Based on four PhRMA reports on the topic of rare 1991 176 disease, the number of agents in development for 2007 303 2011 460 rare diseases has more than tripled, from 133 drugs in 1989 to 460 in 2011. (See Table 3) (Table based on information from PhRMA47)

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According to the PhRMA 2011 report Orphan Drugs in Development for  the Canadian Agency for Drugs and Technologies in Health (CADTH) in Rare Diseases45, there were 460 orphan drugs actively being developed in Canada the US in 2011. Notably, the majority of these drugs were for the  Australia’s Pharmaceutical Benefits Advisory Committee (PBAC) treatment of rare cancers (217). Genetic disorders (67), neurological  Haute Autorité de Santé (HAS) in France disorders (37), and infectious diseases (31) represented the next three  Germany’s Institute for Quality and Efficiency in Health Care (IQWIG) 45 largest therapeutic categories specifically identified.  Scotland’s Scottish Medicines Consortium (SMC)  National Institute for Health and Care Excellence (NICE) in the UK. C. HTA Reimbursement Frameworks for DRD 1) HTA and Reimbursement Perspectives in the DRD Evaluation Table 4 summarizes evolving regulatory and HTA reimbursement trends for the following selected HTA organizations:

PBAC submission guidance LSDP Funding:50 states: “PBAC is aware of, and PBAC looks at the following issues in deeming a submission acceptable sympathetic to, the difficulties for LSDP funding , and in formulating a recommendation to the faced by sponsors of orphan Minister: drugs. Furthermore, the A drug must meet the following criteria: committee does not set a 1) The TGA has approved the drug and its indication for treatment minimum standard for the type of a clinically definable rare disease. and level of evidence or other 2) The disease can be identified with reasonable diagnostic information that can be precision.

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Table 4: Evolving Trends in Regulatory and HTA Reimbursement Perspectives for Selected HTA Organizations Country (HTA Separate Reimbursement If Yes, Details of Process Is Cost-Effectiveness a Required Organization) Review Process for Drugs for Element of the Reimbursement Rare Diseases (yes/no?) Submission? included in a submission to 3) Age-specific life expectancy of affected patients is significantly PBAC. However, it would be reduced, as supported by epidemiological and other study unlawful for PBAC not to evidence acceptable to PBAC. consider comparative costs and 4) PBAC acceptable evidence supports direct and substantial effectiveness.”48 lifespan extension for patient’s treated with this drug. The “rule of rescue” may be 5) PBAC accepted the clinical effectiveness, but rejected the cost- applied as a supplement to effectiveness criteria for listing this drug on the PBS Schedule. orphan drug submissions if the 6) No alternative life-saving drugs are available for hospital in- four delineated factors are patients or listed on the PBS for treating this specific disease. present, however the rule does (Note: Availability of an alternative drug for this condition under not replace consideration of the LSDP does not preclude consideration of this drug as well.) evidence-based comparative 7) There are no suitable, recognized, cost-effective non-drug cost-effectiveness. therapies available for this condition. 8) The annual cost of the drug would be considered an Submissions for rare diseases unreasonable financial burden for the patient or guardian. (Note: that: Annual cost defined as (cost/dose) x (expected # doses/ year/ a. PBAC finds clinically patient)51 effective but ineligible for PBAC also considers and provides advice in consideration of the listing on the PBS due to following , if applicable: cost-effectiveness issues, a. The proposed drug price is compared with the drug’s and effective price in comparable overseas markets. b. meet the eight LSDP- b. The proposed drug price is compared with any comparable specified funding criteria, LSDP-funded drugs. are referred to the LSDP for review and a decision There are also specific patient eligibility criteria for the drug as well as on potential funding using ongoing monitoring requirements that, once approved for therapy, a separate budget. must be met for initial, as well as ongoing, LSDP funding. These are outlined in the various Medical Condition Guidelines Templates (see http://www.health.gov.au/lsdp). France (HAS) No publicly available Not applicable Not applicable (HAS does not information found regarding a examine any economic evidence)52 separate process Germany (IQWIG) No publicly available Not applicable Yes information found regarding a separate process.

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Table 4: Evolving Trends in Regulatory and HTA Reimbursement Perspectives for Selected HTA Organizations Country (HTA Separate Reimbursement If Yes, Details of Process Is Cost-Effectiveness a Required Organization) Review Process for Drugs for Element of the Reimbursement Rare Diseases (yes/no?) Submission? Scotland (SMC) No, the assessment process is Although all drug submissions are required to be comprehensive and Yes same as that for all other drug complete, SMC may choose to be more flexible and allow acceptance submissions; however, some of more uncertainty in the economic case or a higher cost per QALY “modifiers” are acceptable for for orphan drugs. orphan drugs (see details SMC has no formal cost per QALY thresholds for demonstrating cost- column). effectiveness. Cost per QALY is part of a wider judgment of a drug’s value made by SMC. “Modifiers” may be applied in cases of a relatively high cost per QALY, when the committee finds the clinical and economic case to be robust. The assessment may be modified by giving consideration to evidence relating to other factors including, but not limited to:  treatment of a life-threatening disease  substantial increase in life expectancy or quality of life  absence of other therapeutic options  targeting of a medicine for a specific sub-group of patients  reversal versus stabilization of a condition  bridging a gap to a definitive therapy  offering an alternative to an unlicensed drug that is the sole treatment in use for a specific condition. Clinical expert and patient interest group input are also considered for a specific drug, as well as special issues highlighted by the manufacturer.53 UK (NICE/AGNSS)54 Effective April 2013, NICE is The evaluation of technologies by the “highly specialised technologies NICE (Highly specialised again responsible for programme” engages a specific evaluation committee that is an technologies programme) —Yes coordinating the evaluation of independent advisory body. The committee, comprising individuals expensive ultra-rare orphan who work in the National Health Service, pharmaceutical and medical AGNSS — Yes drugs. An interim method that devices industries, patient and caregiver organizations, and relevant builds on the framework used academic disciplines, makes recommendations to NICE for or against by AGNSS has been developed the use of a technology based on its costs and benefits. for the evaluation of such “Given the very small numbers of patients living with these very rare highly specialized drugs. conditions a simple utilitarian approach, in which the greatest gain for Before April 2013, (and since the greatest number is valued highly, is unlikely to produce guidance 2005), NICE referred which would recognize the particular circumstances of these very rare assessments of ultra-orphan conditions. These circumstances include the vulnerability of very small drugs to AGNSS, a specialized patient groups with limited treatment options, the nature and extent national commissioning body. of the evidence, and the challenge for manufacturers in making a

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AGNSS followed a multi-criteria decision analysis framework that used a broad range of criteria beyond cost-effectiveness and holistic view across all of the criteria. The two-step procedure involved an initial assessment of nine entry criteria relating to the rarity of the condition and complexity of its care. Once accepted, the application was assessed based on 12 core criteria organized into the following 4 subgroups:  health gain (clinical safety and risk; severity and ability of patients to benefit; clinical effectiveness and potential for improving health)  societal value (meets needs of patients and society; simulates research and innovation)  reasonable cost (average cost per patient, overall cost impact and affordability, including opportunity cost; value for money when compared with available alternatives)

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AGNSS = Advisory Group for National Specialised Services; CADTH = Canadian Agency for Drugs and Technologies in Health; CDR = Common Drug Review; FDA = Food and Drug Administration; HAS = Haute Autorité de Santé; HTA = health technology assessment; IQWIG = Institute for Quality and Efficiency in Health Care; LSDP = Life Saving Drugs Program; NICE = National Institute for Health and Care Excellence; PBAC = Pharmaceutical Benefits Advisory Committee; PBS = Pharmaceutical Benefits Scheme; SMC = Scottish Medicines Consortium; TGA = Therapeutic Goods Administration; QALY = quality-adjusted life-year.

Examples of International Reimbursement Decisions for Selected DRDs  Ivacaftor (Kalydeco) — for cystic fibrosis with G551D mutation  Eculizumab (Soliris) — for paroxysmal nocturnal hemoglobinuria (PNH) For the same selected international HTA agencies as in the previous table  Sapropterin (Kuvan) — for phenylketonuria (Table 4), Table 5 summarizes reimbursement decisions for the following  Idursulfase (Elaprase) — for Hunter Syndrome (aka MPS II). DRDs:

Table 5: International HTA Agency Reimbursement Decisions for Selected DRDs Kalydeco Soliris Kuvan Elaprase (ivacaftor) (eculizumab) (sapropterin) (idursulfase) Cystic fibrosis with G551D PNH Phenylketonuria Hunter Syndrome (MPS II) mutation Canada March 22, 2013: February 19, 2010: January 26, 2011: December 19, 2007: (CADTH CDR) Recommendation - to list only if Recommendation — do not list at Recommendation — do not list. Recommendation — do not list. both of the following conditions the submitted price. “Eculizumab “Patient details were insufficient “1. While idursulfase has been are met: would not be considered cost- to identify a subpopulation for shown to have a biologic “1. Substantial reduction in effective without a substantial whom sapropterin may provide a effect and improve some price: ivacaftor will not be reduction in the submitted price.”61 significant clinical benefit that is outcomes in patients with considered cost-effective cost-effective.”62 Hunter syndrome, the clinical without a substantial significance of reduction in the submitted its effects is not established. price 2. It is unlikely that idursulfase 2. Clinical criteria for the enters the central nervous discontinuation of ivacaftor system and therefore, it is not treatment in patients who expected to improve the fail to demonstrate a neurological complications of meaningful response must Hunter syndrome. be developed in consultation with CF treatment clinics.”60

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Table 5: International HTA Agency Reimbursement Decisions for Selected DRDs Kalydeco Soliris Kuvan Elaprase (ivacaftor) (eculizumab) (sapropterin) (idursulfase) Cystic fibrosis with G551D PNH Phenylketonuria Hunter Syndrome (MPS II) mutation 3. “…the Committee did not feel that the high cost was justified given the lack of evidence of improvement in clinically important outcomes.”63

Australia July 2013 PBAC agenda: July 2008: PBAC recommendation – July 2012: PBAC recommendation November 2007: PBAC rejected (PBAC, LSDP) requesting section 100 (Highly application rejected due to was a deferral of the submission so application on the basis of Specialised Drugs Program) listing “unacceptably high and highly that discussion could take place unacceptably high cost- or inclusion on the LSDP (decision uncertain estimated cost per with the sponsor regarding price. effectiveness; however for not yet public).64 additional death avoided over a 2- Sponsor working with “PBAC and treatment of MPS II, idursulfase year period.” Also rejected the Department to ensure timely meets criteria for the LSDP.67 application for LSDP access to Kuvan through the consideration.65 LSDP”.66 Available through LSDP for treatment of MPS II.68 Effective May 10, 2010 - PBAC No LSDP listing yet. decision that Soliris for PNH met criteria for LSDP. Available through LSDP for treatment of PNH. 65

France (HAS) November 7, 2012: “The Not found in HAS database as February 4, 2009: “The Not found in HAS database as Transparency Committee reviewed for PNH indication. Transparency Committee reviewed. recommends inclusion on the list A Euro Observer article indicated recommends inclusion on A Euro Observer article indicated of medicines refundable by that the appraisal outcome was “list the list of medicines approved for that the appraisal outcome was National Health Insurance and on with criteria.”70 use by hospitals and various public “list with criteria.” 70 the list of medicines approved for services in the hospital use in the indication indication and at the dosage given “treatment of cystic fibrosis in in the marketing authorisation.”71 patients aged 6 years and older who have a G551D mutation in the CFTR gene (G551D-CFTR mutation)” and at the dosages in the marketing authorisation.”69

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Table 5: International HTA Agency Reimbursement Decisions for Selected DRDs Kalydeco Soliris Kuvan Elaprase (ivacaftor) (eculizumab) (sapropterin) (idursulfase) Cystic fibrosis with G551D PNH Phenylketonuria Hunter Syndrome (MPS II) mutation Germany (IQWIG) November 15, 2012: IQWIG Not in IQWIG database as reviewed Not in IQWIG database as Not in IQWIG database as indicated Kalydeco may breach reviewed reviewed the 50 million Euro per year cost threshold and may require an additional reimbursement evaluation.72 Scotland (SMC) December 7, 2012: October 8, 2010; amended July 11, May 5, 2009: “Advice in the July 6, 2007: “Advice following a “Advice following a full 2011: absence of a submission from the full submission idursulfase submission: ivacaftor (Kalydeco) “Advice following a full submission: holder of the marketing (Elaprase) is not recommended for is not recommended for use eculizumab (Soliris) is not authorisation sapropterin (Kuvan) use within NHS Scotland for the within NHS Scotland. Indication recommended for use within NHS is not recommended for use within long-term treatment of patients under review: treatment of cystic Scotland. NHS Scotland for the treatment of with Hunter syndrome fibrosis in patients age 6 years Indication under review: for the hyperphenylalaninaemia (HPA) in (Mucopolysaccharidosis II, MPS II). and older who have a G551D treatment of patients with PNH. adult and paediatric patients with Idursulfase was approved by the mutation in the cystic fibrosis Evidence of clinical benefit of phenylketonuria (PKU) and for the EMA under exceptional transmembrane conductance eculizumab in the treatment of treatment of circumstances and has been regulator gene. Ivacaftor has patients with PNH is limited to hyperphenylalaninaemia (HPA) in designated an orphan medicinal demonstrated superiority over patients with a history of adult and paediatric patients with product. The manufacturer’s placebo measured by absolute transfusions. tetrahydrobiopterin (BH4) justification of the treatment’s change in forced expiratory In a controlled study in patients deficiency. The holder of the cost in relation to its health volume in one second (FEV1) % with transfusion-dependent PNH, marketing authorisation has not benefits was not sufficient to gain predicted in two phase III, eculizumab reduced the rate of made a submission to SMC acceptance by SMC and, in double-blind randomised haemolysis and improved anaemia regarding this product in this addition, they did not present a studies. The submitting compared to placebo. Uncontrolled indication. As a result we cannot sufficiently robust economic company’s justification of the data suggest that eculizumab recommend its use within NHS analysis.”78 treatment’s cost in relation to its reduces the incidence of thrombosis Scotland.”77 health benefits was not sufficient in patients with PNH. to gain acceptance by SMC and in The manufacturer did not supply addition the company did not any health economic analysis and present a sufficiently robust cost-effectiveness was not economic analysis to gain demonstrated in an independent acceptance by SMC. The licence economic analysis therefore holder had indicated their eculizumab cannot be intention to resubmit.”73 recommended for use within NHS Scotland.”75,76

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Table 5: International HTA Agency Reimbursement Decisions for Selected DRDs Kalydeco Soliris Kuvan Elaprase (ivacaftor) (eculizumab) (sapropterin) (idursulfase) Cystic fibrosis with G551D PNH Phenylketonuria Hunter Syndrome (MPS II) mutation May 10, 2013: “Advice following a resubmission: ivacaftor (Kalydeco) is not recommended for use within NHS Scotland. Indication under review: treatment of cystic fibrosis in patients age 6 years and older who have a G551D mutation in the cystic fibrosis transmembrane conductance regulator gene. Ivacaftor has demonstrated superiority over placebo measures by absolute change in forced expiratory volume in one second (FEV1) % predicted in two phase III, double-blind randomised studies. The submitting company’s justification of the treatment’s cost in relation to its health benefits was not sufficient and in addition the company did not present a sufficiently robust economic assessment to gain acceptance by SMC.”74 UK (NICE/AGNSS) December 19, 2012: “Ivacaftor AGNSS - Not reviewed AGNSS – No information found; AGNSS – No information found; will be funded by the NHS in NICE – Not reviewed (Topic assuming not reviewed assuming not reviewed England for all patients aged 6 selection process between July NICE – Not reviewed (Topic NICE – Not reviewed years and over with cystic fibrosis 2006 and December 2008 wave 15- selection process between July (no record of consideration on and the G551D gene mutation.” 21: rejected prior to topic selection 2006 and December 2008 wave NICE website) Kalydeco was reviewed by the panel). Not referred to AGNSS. 15-21: rejected post topic Clinical Priorities Advisory Group selection panel, pre-scoping)83 (CPAG), which was established in As an aside - Soliris for atypical September 2012 specifically for hemolytic uremic syndrome (aHUS) evaluation of this new drug, on indication: The positive behalf of the four Specialised recommendation for Soliris in aHUS

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Table 5: International HTA Agency Reimbursement Decisions for Selected DRDs Kalydeco Soliris Kuvan Elaprase (ivacaftor) (eculizumab) (sapropterin) (idursulfase) Cystic fibrosis with G551D PNH Phenylketonuria Hunter Syndrome (MPS II) mutation Commissioning Groups in made by AGNSS was rejected in England. The group adopted the January 2013 by the UK government decision-making framework used and the reimbursement review has by AGNSS. The decision was subsequently been referred to NICE. based on a review of the drug’s Review estimated to be completed clinical and cost-effectiveness.79 in the spring of 2014.80-82

AGNSS = Advisory Group for National Specialised Services; aHUS = atypical hemolytic uremic syndrome; BH4 = tetrahydrobiopterin; CPAG = Clinical Priorities Advisory Group; CADTH = Canadian Agency for Drugs and Technologies in Health; CDR = Common Drug Review; EMA = European Medicines Agency; HAS = Haute Autorité de Santé; HPA = hyperphenylalaninemia; IQWIG = Institute for Quality and Efficiency in Health Care; LSDP = Life Saving Drugs Program; NICE = National Institute for Health and Care Excellence; PBAC = Pharmaceutical Benefits Advisory Committee; PNH = paroxysmal nocturnal hemoglobinuria; PKU = phenylketonuria; SMC = Scottish Medicines Consortium.

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2) Canada’s Publicly Funded Drug Programs’ DRD- mechanism(s) of action of the drug candidate under specific Evaluation Frameworks for Evaluating DRD review.8 Funding Step 3 – Assesses the potential effectiveness of the a. Ontario’s DRD Evaluation Framework drug, based on the best available evidence The Ontario Ministry of Health and Long-Term Care This step evaluates the clinical evidence supporting developed a separate evaluation framework for the drug candidate. This includes direct clinical trial assessing funding of DRDs under its publicly funded data on the drug and indirect evidence (e.g., from drug program. A framework was needed due to the other disease conditions) where appropriate. When absence of a national strategy for reviewing and only sparse or questionable clinical data are evaluating rare disease drugs and because of a available, use of the Bradford Hill criteria for historic and ongoing need to address patient access causality, adapted for treatment assessment, is to these drugs in Ontario.84 This evaluation is applied as a tool in assessing whether the drug alone conducted by a separate five-member DRD Working potentially caused the reported patient benefits or Group, that has physician, economist, pharmacist, not.86 and geneticist representation and reports directly to the Executive Officer of the Ontario Public Drug Step 4 – Evaluates budget and cost impact Programs.85 There are no restrictions on the types of Cost-effectiveness analyses are not conducted, nor is rare diseases considered for evaluation under this cost-effectiveness a deciding factor in evaluating a framework, and requests for funding consideration drug under review by this framework; however, the under the DRD framework may be submitted by affordability of the product is taken into manufacturers or physicians.84 consideration in formulating the final decision.

The evaluation framework uses an evidence-based Step 5 – Identifies whether any additional follow- process and considers the best achievable evidence up data is needed for the particular drug under review, with indirect This step identifies whether and what types of other evidence taken into consideration when necessary. studies may be required to generate more Predictive models identifying the natural progression information. of a disease, where a drug might provide the treatment effect, and the patients most likely to To date, Ontario’s DRD Evaluation Framework has benefit from treatment, are used to inform the been used for the evaluation of seven DRD funding decisions.85 submissions: five drugs indicated for genetic lysosomal storage disorder drugs, one drug for skin The framework consists of five steps:8,84,85 cancer, and one drug for a group of genetic auto- inflammatory diseases.85 Compared with the time Step 1 – Assesses whether a submitted disease taken to perform a regular drug review, Ontario’s meets the framework’s criteria of “rare” experience has shown that DRD reviews take a Determination of whether a DRD is eligible for longer time to complete. This can be attributed to review under the framework is determined by: the increased amount of time needed to a) disease incidence rate of fewer than 1 in comprehensively review the disease state and drug, 150,000 live births or new diagnoses per year as well as the time required to develop a predictive b) lack of availability or feasibility of adequately disease model.87 powered randomized controlled trials detecting clinically relevant outcomes, given the rarity of the b. Alberta’s Rare Diseases Drug Program disease. On April 1, 2009, Alberta launched a Rare Disease

Drug Program for eligible Albertans under its publicly Step 2 – Gains an understanding of the natural funded drug plan. This program was developed for history of the disease ethical and compassionate reasons to help affected This step entails a review of the disease state itself, individuals with the exceptionally high costs of rare including its presentation, progression over time, disease drugs.88 For the purposes of this program, a underlying mechanism, and consequences, as rare disease is defined as a genetic lysosomal background information for understanding the storage disorder occurring in fewer than 1 in

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50,000 Canadians, as determined by Alberta Health.7 included) costs are expected to be between $1,500 Thus this program reviews requests only for the and $50,000. Outpatients’ applications for drugs specified lysosomal storage disease category of rare used to treat rare clinical conditions (excluding diseases, which includes, for example, Fabry disease, oncology indications) are eligible for assessment if Pompe disease, and Gaucher disease. the total drug cost is expected to be less than $100,000 per year. Specific funding criteria are used Submitted applications are reviewed by Alberta’s to objectively review requests on a case-by-case Rare Disease Clinical Review Panel, which is a basis. If approved, funding is provided for an agreed Ministry-appointed panel consisting of rare-disease- upon duration beyond which resubmission would be treating specialists and other health care required. professionals with related clinical expertise. The request form, to be completed by a specialist Rare Disease Drug Coverage Applications can be physician working at an Alberta Health Services submitted for an individual patient by their “rare facility and actively treating a patient for a rare disease specialist,” as defined by each drug’s clinical condition, requires the provision of the eligibility criteria. When applying for coverage of a following information: rare disease drug, applicants must consent to a  details about the requested drug (indication, number of conditions should coverage be approved. dose, frequency, duration of therapy, costs) These conditions are as follows:  whether any alternative therapies exist, have a) Conditional initial and continued coverage are been tried, or ruled out dependent upon clinical outcomes.  providing evidence that supports use of the drug b) Ongoing clinical outcome monitoring is for the requested indication mandatory.  details about objective measurable clinical c) Inadequate patient response or deterioration, as outcomes and when they would be expected defined by pre-established withdrawal criteria for a to occur specific drug and/or as assessed by the program’s  information about discrete indicators of clinical review panel, will dictate coverage treatment failure and that therapy should be discontinuation. discontinued.91

Note that the presence of a significant illness likely Specific details regarding funding criteria or decision- to affect life expectancy, outside of the rare disease making frameworks for Alberta’s Rare Disease Drug itself, is considered a contraindication to the rare Program or STEDT could not be found in publicly disease funding.7 available information.

Final coverage decisions for rare disease drug d. British Columbia’s Program for DRD Funding funding are made by Alberta’s Minister of Health, Evaluation and the Minister “may list a drug product under this section when the Minister considers it in the public No publicly available information was found interest to do so.”7 regarding British Columbia’s public drug plan’s DRD funding evaluation framework. c. Alberta’s Short Term Exceptional Drug Therapy (STEDT) Summary In addition, On March 1, 2012, Alberta’s provincial government announced a new Short Term DRD Regulatory Trends for Key Regulators Exceptional Drug Therapy (STEDT) program that US allows funding consideration for certain therapies Since the institution of the 1983 US FDA Orphan without current public or private funding Drug Act, the number of orphan drug designations 89,90 options. and approvals between 1984 and 2010 remained generally constant, with an average of 10 per year; Specialist physicians can submit requests to fund however, as the total number of US drug approvals high-cost non-formulary drugs for rare conditions for has been declining since the peak in the 1990s, the in-patients whose drug therapy (oncology drugs proportion of new drug approvals attributed to

Drugs for Rare Diseases: Evolving Trends in Regulatory 26 and Health Technology Assessment Perspectives Environmental Scan orphan drugs has risen from 17% in the 1990s to and would represent an estimated $127 billion in over 35% between 2008 and 2010, a trend that is sales. expected to continue. The majority of approvals have been for oncology drugs. It is estimated that Health Technology Assessment 15.5% of US orphan drug designations made since Reimbursement Frameworks for DRD 1983 have been approved. Of the six selected HTA organizations scanned for European Union publicly available information, only one (NICE) has a DRD-specific evaluation framework. Most agencies Since the start of the EU Orphan Regulation in 2000 (CDR at CADTH, PBAC and LSDP in Australia, and until 2012, the number of orphan drug designations by the EC has risen steadily. Almost 1,100 SMC in Scotland) currently evaluate DRDs through designations have been granted, starting with 14 in their standard processes, with some allowing for more flexibility in their cost-effectiveness thresholds the first year to 148 in 2012, with the majority of when evaluating DRDs. designations being for oncology drugs. An estimated 7% of all orphan drug designations granted since The Ontario Ministry of Health and Long-Term Care 2000 have received centralized marketing has a well–developed separate evaluation authorization for the EU. framework specific to DRDs. Using an evidence-

Canada based process, the decision-making framework considers the best achievable evidence for the drug Until October 2012, Canada had no policies and no under review, taking indirect evidence into regulatory framework for orphan drugs. Currently, there is a Health Canada draft discussion document consideration when necessary. Predictive models for an orphan drug regulatory framework that would help inform funding decisions by identifying the natural progression of a disease, where a drug may define an orphan drug as one that meets certain provide the treatment effect, and the patients most criteria including disease prevalence and disease severity. Sponsors of orphan drugs would submit likely to benefit from treatment. applications for orphan drug designation to Health Alberta has a Rare Disease Drug program, which Canada. If granted, sponsors would be eligible for specified regulatory incentives. allows individuals to apply for funding for drugs that fall under the lysosomal storage disease category of rare diseases. In addition, a Short Term Exceptional Biopharmaceutical Industry Pipeline for DRD Drug Therapy program for funding high-cost non- The DRD pipeline is rapidly evolving, and grows formulary drugs for rare conditions is available for almost daily. In 2012, worldwide orphan drug sales both in-patients and outpatients. British Columbia’s totalled $83 billion representing approximately 13% public drug plan has a DRD framework, but no of the worldwide prescription sales (excluding publicly available information was found. generics). This is expected to rise to 15.9% by 2018

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Appendix 1: Rare Disease Drug Cost Examples (in 2010 US dollars)

Drug and Company Rare Disease Annual Cost (US dollars) Soliris (eculizumab) PNH $409,500 Alexion Elaprase (idursulfase) Hunter syndrome $375,000 Shire Naglazyme (galsulfase) Maroteaux-Lamy syndrome (MPS VI) $365,000 BioMarin Cinryze (C1 esterase inhibitor, human) Hereditary angioedema $350,000 ViroPharma Myozyme (alglucosidase alfa) Pompe disease $300,000 Genzyme PNH = paroxysmal nocturnal hemoglobinuria; US = United States. (Table based on data from Forbes article21)

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Appendix 2: US and EU Orphan Drug Enabling Legislation, Designation Criteria, and Industry Incentives

Enabling Legislation Criteria for Orphan Drug Designation Incentives for Pharmaceutical Industry US FDA Orphan Drug Act  The drug (expanded to include biologics, 1. Clinical research protocol assistance 1983 (and 1984, medical devices, medical foods) is 2. Seven (7) years of market 1985, 1988, 1992 indicated for treatment, diagnosis, or exclusivity beginning at the date of amendments) prevention of a disease or condition FDA approval for the designated affecting fewer than 200,000 people in orphan indication the US at the time of the orphan drug designation submission; or affects more 3. Availability of research grants than 200,000 people in the US but costs 4. 50% tax credits for clinical research of developing the drug and making it costs available in the US not expected to be offset by US sales of the drug in the first 5. Waiving of new drug application seven years. filing fees  A product must not have been previously 6. Can apply for accelerated review 22,95 approved for the disease/condition for (not specific to orphan drugs) which orphan drug designation is being requested.  Multiple sponsors can receive orphan drug designation for the same drug and indication; marketing exclusivity would go to the first sponsor to receive marketing approval.  The same drug can be made available by other sponsors for different uses during the seven-year period of exclusivity. Regarding market exclusivity:  A drug that is similar to another authorized orphan drug for the same rare disease indication must demonstrate clinical superiority  The FDA cannot approve the same drug for the same indication from a competitor during the period of market exclusivity unless the sponsor of the first authorized orphan product is unable to provide sufficient supply of the product, or the first sponsor provides its consent.1,92-94

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Enabling Legislation Criteria for Orphan Drug Designation Incentives for Pharmaceutical Industry EMA The Orphan  Only medicinal products for human use 1. Protocol assistance at a reduced Regulation 1999 – can apply for orphan drug designation charge – scientific advice from the (EC) No 141/2000 (no medical devices, nutritional Agency specifically for orphan (and (EC) No supplements, or dietary products). medicines regarding types of 847/2000)  “Must be intended for the treatment, studies needed to support a prevention, or diagnosis of a disease that medicine’s quality, benefits, and is life-threatening or chronically risks, and information on significant debilitating. benefit of the medicine  The prevalence of the condition in the EU 2. Access to the centralized must not be greater than 5 in 10,000, or authorization procedure for the EU it must be unlikely that marketing the (single application to EMA, resulting medicine would generate sufficient in single opinion and decision from returns to justify the investment needed EC which is valid in all EU member for its development. states).  No satisfactory method of diagnosis, 3. Ten (10) years of market exclusivity prevention, or treatment of the (extended by 2 years for medicines condition concerned can be authorized, that also comply with required or, if such a method exists, the medicine pediatric investigations) must be of significant benefit [defined as 4. Fee reductions for regulatory a clinically relevant advantage or a major activities – including protocol contribution to patient care]96 to those assistance, marketing authorization affected by the condition.”2 applications, inspections before  A new indication for an already authorization, applications for authorized product is eligible for orphan changes to market authorizations designation application. made after approval, reduced  Orphan designation can be granted to annual fees. multiple sponsors for the same product 5. Additional incentives for micro, indicated for the same disease or small, and medium-sized condition. enterprises – including administrative and procedural Regarding marketing exclusivity: assistance, and fee reductions 6. Can apply for accelerated review  Once marketing authorization is granted (not specific to orphan drugs) 7. Potential for incentives/grants by to an orphan product, another 96,97 application for marketing authorization member states or EC cannot be accepted, granted, or an existing authorization extended for the same therapeutic indication for a “similar medicinal product” (meaning a product with similar active substance(s) indicated for the same indication). Note that a “similar active substance,” is identical, or one having the same principal, but not necessarily all, molecular structural features, and that acts by the same mechanism of action.  A marketing authorization for another orphan product can be granted if:  The original orphan product marketing authorization holder MAH consents; or

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Enabling Legislation Criteria for Orphan Drug Designation Incentives for Pharmaceutical Industry the original MAH cannot supply the product in sufficient quantity to meet demand, or the new applicant for a medicinal product similar to the authorized orphan product can demonstrate that it is safer, more effective, or otherwise clinically superior2,96-98

EC = European Commission; EMA = European Medicines Agency; EU = European Union; FDA = Food and Drug Administration; MAH = marketing authorization holder; US = United States.

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Appendix 3: Orphan Drug Enabling Legislation, Designation Criteria, and Industry Incentives

Legislation and US (FDA) EU (EMA) Australia (TGA) Japan (MHLW) Provisions Orphan Drug Orphan Drug Act Orphan Regulation Orphan Drug Orphan Drug Legislation/Policy 1983 1999 – (EC) No Program 1997 Regulation 1993 141/2000 Marketing 7 years 10 years (extended 5 years 10 years Exclusivity Period by 2 years for medicines that also comply with required pediatric investigations) Accelerated Yes Yes Yes Yes Evaluation Availability Application or Yes Yes Yes No Other Regulatory Fee Reductions or Waivers Scientific Advice Yes Yes Yes Yes (Research Protocols, Technical Assistance, etc.) Tax Incentives 50% tax credits Tax credits developed No Tax Exemption Law for clinical by each member (12% of expenses) research costs state Other Clinical research Access to EU Extension of funding through centralized registration validity Orphan Products authorization process period Grants Program Additional incentives Development costs for micro, small, and partially reimbursed medium-sized enterprises – including administrative and procedural assistance, and fee reductions

EMA = European Medicines Agency; EU = European Union; FDA = Food and Drug Administration; MHLW = Ministry of Health, Labour, and Welfare; TGA = Therapeutic Goods Administration; US = United States. (Table based on data from three reports.22,30,31)

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Drugs for Rare Diseases: Evolving Trends in Regulatory 39 and Health Technology Assessment Perspectives Environmental Scan

Cite as: Loorand-Stiver L. Drugs for Rare Diseases: Evolving Trends in Regulatory and Health Technology Assessment Perspectives [Environmental Scan, Issue 42]. Ottawa: Canadian Agency for Drugs and Technologies in Health; 2013.

***************** CADTH takes sole responsibility for the final form and content of this environmental scan. The statements and conclusions in this environmental scan are those of CADTH.

Production of this report is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Prince Edward Island, Saskatchewan, and Yukon. The Canadian Agency for Drugs and Technologies in Health takes sole responsibility for the final form and content of this report. The views expressed herein do not necessarily represent the views of Health Canada or any provincial or territorial government.

***************

Disclaimer: The Environmental Scanning Service is an information service for those involved in planning and providing health care in Canada. Environmental Scanning Service responses are based on a limited literature search and are not comprehensive, systematic reviews. The intent is to provide information on a topic that CADTH could identify using all reasonable efforts within the time allowed. Environmental Scanning Service responses should be considered along with other types of information and health care considerations. The information included in this response is not intended to replace professional medical advice nor should it be construed as a recommendation for or against the use of a particular health technology. Readers are also cautioned that a lack of good quality evidence does not necessarily mean a lack of effectiveness, particularly in the case of new and emerging health technologies for which little information can be found but that may in future prove to be effective. While CADTH has taken care in the preparation of the report to ensure that its contents are accurate, complete, and up to date, CADTH does not make any guarantee to that effect. CADTH is not liable for any loss or damages resulting from use of the information in the report. Copyright: This report contains CADTH copyright material. It may be copied and used for non-commercial purposes, provided that attribution is given to CADTH. Links: This report may contain links to other information available on the websites of third parties on the Internet.

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Drugs for Rare Diseases: Evolving Trends in Regulatory 40 and Health Technology Assessment Perspectives