Drugs for Rare Diseases: Evolving Trends in Regulatory and ... · Drugs for Rare Diseases: Evolving Trends in Regulatory and Health Technology Assessment Perspectives Author: Canadian

Drugs for Rare Diseases: Evolving Trends in Regulatory 1 and Health Technology Assessment Perspectives

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

Drugs for rare diseases (DRDs), also referred to as orphan drugs in some jurisdictions, are typically small-molecule drugs or biopharmaceuticals (referred to collectively herein as “drugs”) used to treat rare diseases. Due to a shift in the focus of the biopharmaceutical industry’s research and development priority from blockbuster to niche drugs, the DRD pipeline and the number of marketed DRDs are expanding. The purpose of this Environmental Scan is to provide an overview of the DRD landscape and their implications both globally and in Canada. This information may assist drug policy decision-makers, as well as stakeholders, in understanding the landscape of DRDs and key issues related to the review and reimbursement of DRDs. Definitions for rare diseases differ based on various jurisdictions’ related legislation or policies, and thus, there is no single definition for rare diseases that is accepted worldwide. These definitions typically include a criterion of disease incidence or prevalence. For example (see also summary Table 1):

For purposes of orphan drug designation, the United States (US) Food and Drug Administration (FDA) considers a rare disease to be one that affects fewer than 200,000 Americans.

1

Orphan drug designation by the European Medicines Agency (EMA) uses a condition prevalence in the European Union (EU) of not greater than 5 in 10,000 people affected (i.e., 1 in 2,000).

2

In Japan (Ministry of Health, Labour, and Welfare), granting of orphan drug status is considered for drugs meeting specific criteria,

including a disease affecting fewer than 50,000 people in Japan.

3,4

Australia’s Therapeutic Goods Administration, for purposes of orphan drug designation, states that a rare disease is one with a prevalence of fewer than 2,000 people (in a total population of 18 million, approximately 1 in 10,000).

5

In South Korea (Ministry of Food and Drug Safety), rare diseases are defined as diseases affecting fewer than 20,000 people.

6

Taiwan’s Department of Health classifies a rare disease as one that is prevalent in fewer than 1 in 10,000 people of the population, difficult to diagnose and treat, with a genetic origin.

6

For Alberta’s publicly funded drug plan, a rare disease is defined as a genetic lysosomal storage disorder that occurs at a rate of fewer than 1 per 50,000 Canadians, as determined by Alberta Health.

7

Ontario’s publicly funded drug plan’s working definition of rare disease includes those with an incidence rate of fewer than 1 in 150,000 live births or new diagnoses per year.

8

Generally, rare diseases are considered to be severe, progressive, degenerative, life-threatening, or chronically debilitating, with a low prevalence.

9,10

A large proportion (50%) of rare diseases have their onset in childhood.

11 The majority (80%) of rare

diseases are genetic in origin, affecting between 3% and 4% of births,

9,12 or have a genetic component.

10

Allergic, infectious (bacterial or viral), degenerative, proliferative and environmental (e.g., chemicals, radiation), or combinations of genetic and environmental causes have been recognized as well, yet in other cases specific causes remain unknown.

10,12-14 A large percentage of rare diseases

undergoing active research are cancers13

; however, DRDs encompass all therapeutic areas.

11

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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), formerly known as the Korea Food & Drug Administration (KFDA)

Affects < 20,000 people

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 only a small number of individuals, it is estimated that there are between 6,000 and 8,000 distinct rare diseases worldwide,

15 with almost weekly reporting

of newly identified disorders,14

and approximately 250 new diseases identified annually.

6 Prevalence of

rare diseases can vary among the populations of different countries.

13 According to the Canadian

Organization for Rare Diseases (CORD),16

rare diseases affect 1 in 12 or approximately 2.8 million Canadians. Thus, there is a “paradox of rarity”

9 in

that although individually the diseases are rare, a significant portion of a country’s population can be affected. In addition, others may be at risk for or have a rare disease; however, they remain unaware or undiagnosed.

17 Thus, collectively, rare diseases

represent a substantial health burden both nationally in Canada, as well as worldwide, with an estimated 350 million people affected globally.

18

Given the nature of rare diseases, they can significantly affect a patient’s autonomy and quality of life.

19,20 For the majority of these diseases, there

are currently no specific treatments available to cure or modify the disease,

10 as compared with more

common diseases or conditions like diabetes or hypertension. Furthermore, drug therapies that have been developed for rare diseases are typically expensive, with a number of drugs having an average per patient annual cost that exceeds US$350,000 (in 2010 dollars).

21 (See Appendix 1.)

“Above and beyond worrying about expensive therapies, patients diagnosed with a rare disease are often surprised to learn that there is limited scientific knowledge about the causes and natural history of their condition and little or no ongoing research.”

22

With or without available treatments, patients face significant challenges in obtaining appropriate care due to factors such as a lack of physician knowledge about rare diseases or symptoms of a rare disease being masked by or confused with other conditions, both of which can lead to significant delays in arriving at an accurate diagnosis.

23 According to

patients with rare diseases surveyed for a recent report

20, it takes US patients an average of 7.6 years

and United Kingdom (UK) patients an average of 5.6 years to receive an accurate diagnosis, typically involving as many as eight physicians (four primary care and four specialists). In addition, two to three misdiagnoses are typical before arriving at a final diagnosis. Once patients are correctly diagnosed, they often face inequities and challenges in accessing any existing approved, and typically costly, treatments. Thus patients, their families, and/or caregivers can be heavily burdened both financially and emotionally as they seek accurate diagnosis, information, support, and treatments for these rare conditions.

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Objectives

Grouped under three subtopics, this Environmental Scan will address the following questions: A. DRD Regulatory Trends for Key Regulators

(US FDA, EMA, Health Canada) 1) What has been the trend for orphan drug

designation and approvals in the US since the institution of the 1983 US FDA Orphan Drug Act?

2) What has been the trend for orphan drug designation and approvals by the EMA since the Orphan Regulation came into force in 2000?

3) What is the status of an orphan drug regulatory framework in Canada?

B. Biopharmaceutical Industry Pipeline for DRD

1) How is the DRD pipeline evolving? 2) What is the current and predicted market

volume of DRDs, and their financial effect? C. Health Technology Assessment Reimbursement

Frameworks for DRD 1) How are health technology assessment

(HTA) and reimbursement perspectives evolving in the DRD evaluation area? (i.e., are DRD-specific evaluation frameworks used, and is cost-effectiveness a mandatory consideration?)

2) Do any of Canada’s publicly funded drug plans use a rare-disease drug-specific evaluation framework to evaluate DRD funding?

Findings

A. DRD Regulatory Trends for Key Regulators (US FDA, EMA, Health Canada)

Under normal drug marketing conditions, the pharmaceutical industry historically lacked incentive to commit the high costs associated with developing a new drug, estimated to be in the millions or

billions per drug,24-26

to the small number of patients suffering from a specific rare disease. Expected product sales would be inadequate to cover the costs of bringing the drug to the market, making such development financially unviable for industry.

27

However, during the past 30 years, research, development, and availability of innovative drugs to treat rare diseases have been enhanced through the introduction of orphan drug legislation and associated orphan drug policy economic incentives.

28

Since the first orphan drug legislation was introduced in 1983 in the US (the Orphan Drug Act), other countries, including Singapore (1991), Japan (1993), Australia (1997), the EU (1999), Taiwan (2000), and South Korea (2003), have also enacted regulatory frameworks for developing orphan drugs.

6,22,29 Examples of incentives for industry to

research and develop drugs to treat rare diseases vary per country and include research protocol assistance, tax incentives, expedited regulatory reviews, reducing or waiving drug application fees, tax credits, and defined periods of market exclusivity.

22,30,31 (See also Appendix 2.)

Orphan Drug Designation and Approval Trends in the US

The US Orphan Drug Act (1983) has been highly successful in incentivizing the development of orphan drugs.

32 In the eight to ten years before its

enactment, the FDA had approved only ten rare disease drugs for marketing.

33 According to the US

FDA Orphan Drug Designations and Approvals database on August 6, 2013,

34 since 1983 to the end

of 2012 a total of 2,740 orphan drug designations have been made (note that this figure does not exclude designations that have been withdrawn) and 427 of these designated drugs had received marketing approval. Based on these figures, approximately 15.5% of US orphan drug designations have been approved. It is noteworthy that the US FDA definition of a DRD has not been adjusted for US population growth since 1983. Figure 1 summarizes the number of orphan drug designations and unique orphan drug approvals from 1984 to 2011.

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

Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews: Drug Discovery 11(4):267-8, Figure 1, copyright 2012. http://www.nature.com/nrd/index.html

From an average of 63 designations per year in the 1990s, the number of US orphan drug designations has doubled to an average of 126 designations per year between 2001 and 2010, reflecting increased biopharmaceutical industry interest in developing drugs to treat rare diseases. At an average of 10 approvals per year, the number of orphan drug approvals between 1984 and 2010 has remained relatively constant; however, as the total number of US drug approvals has been declining since the peak in the 1990s, the proportion of new drug approvals attributed to orphan drugs has risen from 17% in the 1990s to over 35% between 2008 and 2010, a trend that is expected to continue.

36

Figure 2 provides a breakdown of US orphan drug approvals by therapeutic area from 2006 to 2011. The majority of approvals (33%) were for oncology products; the next largest therapeutic categories, accounting for 17% of approvals each, were gastrointestinal disorders and inborn errors of metabolism, and neurological conditions. Immunological diseases and rheumatology disorders each represented 8% of approvals for this time period. The remaining 17% of approvals were other therapeutic areas, each representing less than 5%.

36

Orphan Drug Designation and Approval Trends in the EU

In the year 2000, EU orphan drug legislation, the Regulation on Orphan Medicinal Products (Regulation (EC) No 141/2000 of December 16, 1999), came into force. As with the US Orphan Drug Act, its intention was to offer incentives to industry for developing and marketing drugs to diagnose, treat, or prevent rare conditions.

37

The number of orphan drug designations granted by the European Commission for the EU has increased steadily over the first 12 years of the orphan drug program. From 14 designations granted in the initial year to a total of 148 granted designations in 2012, a total of almost 1,100 designations (not excluding expiries or withdrawals) have been granted from 2000 to 2012 inclusive.

38 These orphan drug

designations correspond to a total of 79 individual drugs that have received centralized marketing authorization for the EU from 2000 to 2012, representing approximately 7% of all orphan drug designations.

38 (See Figure 3) Note that, following

EMA central authorizations, individual EU member states are responsible for the funding of orphan drugs in their various jurisdictions.

http://www.nature.com/nrd/index.html

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

Reprinted by permission from Macmillan Publishers Ltd: Nature Reviews: Drug Discovery 11(4):267-8, Figure 3, copyright 2012. http://www.nature.com/nrd/index.html

Figure 3: EU Orphan Drug Designations Granted and Approved;

Individual Drugs Approved for Marketing (2000 to 2012)

(Figure 3 based on data retrieved from European Commission Register of Designated Orphan Medicinal Products on April 16, 2013

38)

0

20

40

60

80

100

120

140

160Number of Orphan DrugDesignations Granted(for individual indications)BAR ON LEFT

Number of Orphan DrugDesignations Approved forMarketingMIDDLE BAR

Number of Individual DrugsApproved for Marketing(a single drug may have multipleapproved designations for differentindications)BAR ON RIGHT

GI, inborn errors of metabolism 17%

Oncology 33%

Neurology 17%

Rheumatology 8%

Hematology 8%

Other 17%

http://www.nature.com/nrd/index.html

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For the years 2000 to 2011, Figure 4 below illustrates the distribution by various therapeutic areas for which the EMA’s Committee on Orphan Medicinal Products (COMP) provided positive orphan drug designation opinions to the European Commission (EC) for approval (as opposed to orphan drug designations granted by the EC; however, the majority of positive opinions from COMP are typically adopted by the EC). The most common

therapeutic area for positive orphan drug designation opinions from COMP was oncology (41%), followed in decreasing order by musculoskeletal and nervous system (12%) and also metabolism (12%), cardiovascular and respiratory (8%), immunological (7%), anti-infectious (4%), and hematology drugs (3%). Therapeutic categories individually representing less than 3% of the total 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 for Canada

Until recently, Canada has had no established policies or legislative framework specifically for rare disease drug development and approval. On October 3, 2012, the federal government announced the development of an orphan drug framework for Canada.

40 This legislative framework

would be life-cycle-based, encompassing the designation, authorization, and post-market monitoring of orphan drugs, as well as incentivizing related innovative research in Canada.

41

Health Canada has since developed a draft discussion document proposing a comprehensive orphan drug framework with a goal of providing Canadians with access to orphan drugs without

compromising their safety. The document outlines an internationally aligned orphan drug regulatory scheme that aims to provide transparency in gathering and sharing orphan drug information with all stakeholders (including patients, health care professionals, researchers, and payers), as well as international regulatory partners.

42

The Health Canada draft discussion document for the orphan drug regulatory framework

42 proposes

defining an orphan drug as one that meets a number of criteria as follows: a drug “intended for the diagnosis, treatment,

mitigation or prevention of a life-threatening, seriously debilitating, or serious and chronic disease or condition affecting not more than five in ten thousand persons in Canada, and

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the drug is not currently authorized by the Minister or if currently authorized, it will provide a potentially substantial benefit for the patient distinguishable from the existing therapy.”

42

In keeping with orphan drug regulatory frameworks in other countries, sponsors would be asked to submit applications for orphan drug designation to Health Canada. Those meeting the application requirements, which include Health Canada’s definition of an orphan drug, would qualify for the formal granting of an orphan drug designation. In addition, Health Canada also proposes that it would recognize orphan drug designations made by other recognized international regulatory agencies (e.g., the US FDA, EU EMA). A Health Canada orphan drug designation would subsequently provide drug sponsors access to a number of proposed regulatory incentives, including: scientific and clinical trial protocol advice by

Health Canada or in-common with international regulators

priority review of the drug submission regulatory fee reductions (for small to medium

enterprises) linkage with the existing eight-year market

exclusivity post approval (plus an additional six months for drugs with qualifying pediatric study results).

In order to promote orphan drug research, innovation, and increased potential for drugs to successfully reach the market, Health Canada’s proposed orphan drug regulatory framework would be aligned with other jurisdictions in that it would allow:

granting of orphan drug designations to multiple sponsors submitting applications for the same drug indicated for the same rare disease

granting of multiple orphan drug designations for different rare diseases to a single drug.

Due to the large number of identified rare diseases, Health Canada recognizes that it will not always have the necessary in-house scientific and medical expertise to evaluate all DRD regulatory submissions. Therefore, when necessary, the framework indicates that Health Canada will seek advice from external experts to assist in making the best possible regulatory decisions for these drugs. In addition, patient input will be sought in order to provide insight into disease severity and level of unmet medical need for a particular rare disease, to be taken into consideration in the regulatory approval process. Before this proposed formal orphan drug regulatory framework, Health Canada had already approved a number of drugs indicated for rare diseases. However, equitable access to these expensive drugs through provincial and territorial publicly funded drug plans remains an issue for Canadian patients.

B. Biopharmaceutical Industry Pipeline for DRD

1) DRD Pipeline

Table 2 provides a snapshot of some identified DRDs in phase II or III of development, or DRDs approved in the US or EU but not in Canada, based on information from drug pipeline reports.

43-45

The DRD pipeline is rapidly evolving, and grows almost daily.

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Table 2: Snapshot of DRD Pipeline

Nonproprietary Name/Code Name (Brand Name)

Company Disease or Condition Phase of Development

Comments

Autoimmune Disorders

Amifampridine (Firdapse in EU)

BioMarin Lambert-Eaton myasthenic syndrome

ECa approved

23/12/2009 EMA orphan drug designation 18/12/2002

Canakinumab (Ilaris)

Novartis Systemic juvenile idiopathic arthritis (SJIA)

FDA approved 29/05/2013

Golimumab (Simponi Aria)

Janssen Biologics (formerly Centocor)

Sarcoidosis Phase II FDA orphan drug designation 21/05/2012

Human gamma globulin (Oralgam)

Latona Life Sciences

Juvenile rheumatoid arthritis

Phase II completed

FDA orphan drug designation 25/05/2001

Human mesenchymal stem cell therapy (Prochymal)

Osiris Therapeutics

Treatment of type 1 diabetes with residual beta cell function

Phase II FDA orphan drug designation 30/04/2010

Infliximab (Remicade)

Janssen Biologics (formerly Centocor)

Chronic sarcoidosis Phase III FDA orphan drug designation 21/05/2003

Rintatolimod (Ampligen)

Hemispherx ME/CFS (also Phase II completed for treatment of AIDS)

Complete response letter from FDA 04/02/2013

Cancer

Algenpantucel-L (HyperActure Pancreas)

NewLink Genetics

Pancreatic cancer Phase III FDA orphan drug designation 21/10/2010

Astuprotimut-R (Zumagev)

GlaxoSmithKline MAGE-A3 positive non-small-cell lung cancer Mage-A3 positive stages IIb to IV malignant melanoma

Phase III Phase III

Bevacizumab (Avastin)

Genentech Ovarian cancer Stomach cancer Fallopian tube cancer

Phase III Phase III Phase III

FDA orphan drug designation 09/02/2006 FDA orphan drug designation 20/11/2009

Cabozantinib (Cometriq)

Exelixis Follicular medullary and anaplastic thyroid carcinoma and metastatic or locally advanced papillary thyroid cancer



Calaspargase pegol (aka EZN-2285)

Sigma-Tau Acute lymphoblastic leukemia

FDA BLA preparation

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Comments

Carfilzomib (Kyprolis)

Onyx Therapeutics

Multiple myeloma FDA approved 20/07/2012

FDA orphan drug designation 18/01/2008 EMA orphan drug designation 03/06/2008

Dabrafenib (Tafinlar)

GlaxoSmithKline BRAF V600 mutation positive stage IIB through IV melanoma

FDA approved 05/29/2013 EC

a approved

26/08/2013


Decitabine (Dacogen) Eisai Acute myeloid leukemia

FDA complete response letter 07/05/2012, EMA approved 20/09/2012


Denosumab (Xgeva)

Amgen Giant cell tumour of bone



EGEN-001 EGEN Ovarian cancer (monotherapy)

Phase II Gene therapy

Elacytarabine Clavis Pharma Acute myeloid leukemia

Phase III

Everolimus (Afinitor)

Novartis Hepatocellular carcinoma

Phase III Anticipated FDA filing 2013

Histamine dihydrochloride (Ceplene)

EpiCept Acute myeloid leukemia

ECa approved

07/10/2008 FDA orphan drug designation 15/12/1999 EMA orphan drug designation 11/04/2005

Lenalidomide (Revlimid)

Celgene Mantle cell lymphoma FDA approved 05/06/2013


Midostaurin (aka PKC412)

Novartis Acute myeloid leukemia

Phase III Anticipated regulatory filing in 2015; for patients who carry a mutated version of the gene encoding FLT3

Paclitaxel, protein (albumin) bound) (Abraxane)

Celgene Stage IIb to IV melanoma Pancreatic cancer

Phase III Phase III

FDA orphan drug designation 1/10/2009 FDA orphan drug designation 03/09/2009

Paclitaxel poliglumex (Opaxio)

Cell Therapeutics-tics Inc.

Glioblastoma multiforme


Pomalidomide (Pomalyst)

Celgene Multiple myeloma FDA approved 08/02/2013


Pralatrexate (Folotyn) Allos Therapeutics

Advanced or metastatic transitional cell carcinoma of the urinary bladder

EMA – CHMP negative opinion 19/04/2012

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Comments

Rindopepimut (aka CDX-110)

Celldex Therapeutics

Newly diagnosed glioblastoma multiforme

Phase III EGFR3-expressing glioblastoma multiforme

Trabedersen (aka AP 12009)

Antisense Pharma

High-grade glioma Pancreatic cancer Malignant melanoma

Phase III (terminated –lack of patients) Phase II Phase II

FDA orphan drug designation 05/06/2002 FDA orphan drug designation 21/07/2009; EMA orphan drug designation 24/07/2009 FDA orphan drug designation 05/06/2002

Cardiovascular Diseases

Imatinib (aka QT1571)

Novartis PAH FDA new drug application withdrawn

FDA postponed Cardiovascular & Renal Drugs Advisory 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

FDA NDA accepted 14/12/2013 (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; Persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH)

Under review by FDA

02/11/2013 Bayer announced submitting NDA to US FDA. 04/08/2013 US FDA granted priority review for both indications

Treprostinil diolamine

United Therapeutics

PAH Rejected twice by FDA

First FDA complete response 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/releasedetail.cfm?releaseid=750550

Genetic Disorders

Alipogene tiparvovec (Glybera)

UniQure Lipoprotein lipase deficiency

ECa approved

25/10/2012 First gene therapy approved for use in Europe Company preparing to file in US, Canada and other markets

Amifampridine (Firdapse)

BioMarin Lambert-Eaton myasthenic syndrome

ECa approved

23/12/2009 EMA orphan drug designation 18/12/2002

http://ir.unither.com/releasedetail.cfm?releaseid=750550

http://ir.unither.com/releasedetail.cfm?releaseid=750550

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Comments

Ataluren (aka PTC124)

PTC Therapeutics Inc.

Nonsense mutation Duchenne muscular dystrophy

Phase IIb Dec 2012: EMA validated a Marketing Authorization 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 (Ferriprox)

ApoPharma Friedreich ataxia


Drisapersen (aka PRO051/GSK2402968)

GlaxoSmithKline, Prosensa

Duchenne muscular dystrophy

Phase III June 2013: granted breakthrough therapy designation by FDA

Elosulfase alfa (aka BMN-110)

BioMarin Mucopolysaccharidosis IVA (MPSIVA; aka Morquio A syndrome)

Under review by FDA and EMA

Eteplirsen Sarepta Duchenne muscular dystrophy

Phase II complete April 2013: discussions of potential application to FDA for accelerated approval of NDA based on Phase II data

Galsulfase (Naglazyme)

BioMarin Mucopolysaccharidosis IV (MPSVI; aka Maroteaux-Lamy Syndrome)

FDA approved 05/31/2005, EC

a

approved 24/01/2006


Lenti-D (autologous CD34+ hematopoietic stem cells transduced with lentiviral vector Lenti-D encoding the human ABCD1 cDNA)

Bluebird Bio Childhood cerebral adrenoleukodystrophy (CCALD)

Phase II/III planned Gene therapy. Plan to initiate a Phase 2/3 clinical study called the ALD-102 Study in CCALD in the US and Europe in 2013. FDA orphan drug designation 19/04/2012 EMA orphan drug designation 06/06/2012

Migalastat (Amigal)

Amicus Therapeutics, GlaxoSmithKline

Fabry Disease Phase III FDA orphan drug designation 25/02/2004; also has EMA (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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Comments

Pegylated recombinant phenylalanine ammonia lyase (PEG-PAL)

BioMarin Phenylketonuria (PKU) Phase II FDA orphan drug designation 08/03/1995 Being developed as potential treatment for patients not adequately controlled by Kuvan.

PF-06460031 (aka GMI-1070)

Pfizer, GlycoMimetics

Vaso-occlusive crisis associated with sickle cell disease

Phase II FDA fast-track status granted FDA orphan drug designation 17/02/2009

Reslizumab (Cinquil) Cephalon Eosinophilic esophagitis (children)

Phase IIb/III FDA orphan drug designation 19/12/2007

Taliglucerase alfa (Elelyso)

Pfizer Type 1 Gaucher Disease FDA approved 05/01/2012

EMA’s CHMP recommended against marketing authorization since prior authorization of Shire’s VPRIV (velaglucerase alfa) continues to benefit from orphan market exclusivity in the EU.

Tirasemtiv (aka CK-2017357)

Cytokinetics ALS Phase IIb FDA fast-track status granted

Hematologic Disorders

Deferiprone (Ferriprox)

ApoPharma Transfusional iron overload due to thalassemia syndromes

FDA approved 14/10/2011 EC

a approved

25/08/1999

Recombinant Factor VIII fusion protein (rFVIIIIFc)

Biogen Idec, Swedish Orphan Biovitrum (Sobi)

Hemophilia A Under review by FDA and TGA

FDA orphan drug designation Submission to EMA once study in children under 12 years of age is complete

Recombinant Factor IX fusion protein (rFIXFc)

Biogen Idec, Swedish Orphan Biovitrum (Sobi)

Hemophilia B Under review by FDA

FDA orphan drug designation

Reslizumab (Cinquil)

Cephalon Hypereosinophilic syndrome

Phase III

Ruxolitinib phosphate (JAKAFI US; JAKAVI Canada)

Incyte Polycythemia vera Phase III Planned FDA filing in 2014

Neurologic Disorders

Amitriptyline/ ketamine (aka EPICEPT NP-1) (AmiKet)

EpiCept Postherpetic neuralgia Phase II completed FDA orphan drug designation 19/01/2010

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

Onabotulinum toxin A (Botox)

Allergan Juvenile cerebral palsy Phase III FDA orphan drug designation 06/12/1991

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Comments

Pridopidine (aka ACR-16 (Huntexil)

Teva (formerly NeuroSearch)

Huntington disease Phase III Advanced-stage clinical studies (conducted in US, EU and Canada) 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 (aka BHR-100)

BHR Pharma Traumatic brain injury Phase III FDA orphan drug designation 03/09/2009

Tirasemtiv (aka CK-2017357)

Cytokinetics ALS Phase IIb Phase IIb potential registration clinical trial (BENEFIT-ALS) results expected early 2014

Clazosentan Actelion Subarachnoid hemorrhage


Clobazam (ONFI)

Lundbeck Lennox-Gastaut syndrome



Dichlorphenamide (DCP)

Taro, University of Rochester

Primary periodic paralyses

Phase III FDA orphan drug designation 02/09/2010

Tasimelteon Vanda Pharmaceuticals

Non-24-hour sleep/wake disorder

Phase III FDA orphan drug designation 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 (aka NP-12) (Zentylor)

Noscira Progressive supranuclear palsy

Phase II FDA fast-track status granted in 2010 FDA orphan drug designation 13/10/2009 EMA orphan drug designation (November 2009)

Other

ATL1103 Isis, Antisense Therapeutics

Acromegaly Phase II 04/10/2013: ATL1103 Phase II trial 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 (Cayston)

Gilead Non-cystic fibrosis bronchiectasis

Phase III Inhalation dosage form FDA orphan drug designation 15/05/2009

http://www.antisense.com.au/wp-content/uploads/downloads/2013/04/ASX-13_-April_-ATL1103_Phase-II-trial_dosing-commenced-final.pdf





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Comments

Chenodeoxycholic acid (Xenbilox)

Sigma-Tau Cerebrotendi-nous xanthomatosis

FDA NDA preparation


Defibrotide Sigma-Tau, Gentium

Hepatic venoocclusive disease treatment after stem cell transplantation

FDA NDA preparation

Ex vivo cultured adult human mesenchymal stem cells (Prochymal)

Osiris Therapeutics

Acute graft versus host disease

Phase III Stem cell therapy; FDA orphan drug designation 14/12/2005

EXN-2279 (aka polyethylene glycol recombinant adenosine deaminase [PEG-rADA])

Sigma-Tau Adenosine deaminase deficiency

Phase III

Glycerol phenylbutyrate (Ravicti)

Hyperion Therapeutics

Urea cycle disorders FDA approved 01/02/2013


rAAv1-CB-hAAT Applied Genetic Technologies Corp.

Alpha-1 antitrypsin deficiency

Phase II Gene therapy; Phase 2b clinical trial will begin in 2014

Teduglutide (Gattex)

NPS Pharmaceuticals

Short bowel syndrome FDA approved 21/12/2012

FDA orphan drug designation 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 Financial Impact

Global Orphan Drug Sales The worldwide orphan drug market is expected to grow significantly in the future. A recently released report

46 forecasts that:

by 2018, global orphan drug sales will grow to $127 billion, and

orphan drugs will represent 15.9% of worldwide prescription sales, excluding generics, by 2018 (as compared with 5.1% in 1998). See Figure 5.

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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 Manufacturers of America (PhRMA),

47 the

organization that represents US-based biopharmaceutical researchers and biotechnology companies, the number of rare disease drugs in development has been rising steadily over the years. Based on four PhRMA reports on the topic of rare disease, the number of agents in development for rare diseases has more than tripled, from 133 drugs in 1989 to 460 in 2011. (See Table 3)

Table 3: Number of Drugs for Rare Disease in Development

Year of PhRMA Report on Rare Disease Medicines

in Development

Number of Medicines in Development

1989 133

1991 176

2007 303

2011 460

(Table based on information from PhRMA47)

http://info.evaluategroup.com/OrphanDrug2013_BSB_LP.html?BSB=TEXT

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According to the PhRMA 2011 report Orphan Drugs in Development for Rare Diseases

45, there were 460 orphan drugs actively being developed in

the US in 2011. Notably, the majority of these drugs were for the treatment of rare cancers (217). Genetic disorders (67), neurological disorders (37), and infectious diseases (31) represented the next three largest therapeutic categories specifically identified.

45

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:

the Canadian Agency for Drugs and Technologies in Health (CADTH) in Canada

Australia’s Pharmaceutical Benefits Advisory Committee (PBAC)

Haute Autorité de Santé (HAS) in France

Germany’s Institute for Quality and Efficiency in Health Care (IQWIG)

Scotland’s Scottish Medicines Consortium (SMC)

National Institute for Health and Care Excellence (NICE) in the UK.

Table 4: Evolving Trends in Regulatory and HTA Reimbursement Perspectives for Selected HTA Organizations

Country (HTA Organization)

Separate Reimbursement Review Process for Drugs for Rare Diseases (yes/no?)

If Yes, Details of Process Is Cost-Effectiveness a Required Element of the Reimbursement Submission?

Canada (CADTH CDR) No, regular submission and review process through CDR is currently followed.

Not applicable Yes

Australia (PBAC, LSDP) No specific DRD evaluation program for Australia, but potential options for funding DRDs through LSDP, following PBAC acceptance as clinically effective, but listing rejected due to failing required cost-effectiveness criteria. PBAC submission guidance states: “PBAC is aware of, and sympathetic to, the difficulties faced by sponsors of orphan drugs. Furthermore, the committee does not set a minimum standard for the type and level of evidence or other information that can be

PBAC has a “rule of rescue,” with the following four criteria/factors:

49

1. There are no drug or non-drug treatments available in Australia for patients with the specific medical condition.

2. The medical condition is severe, progressive, and expected to result in premature death.

3. The medical condition applies to a very small number of patients. 4. The proposed drug qualifies as a rescue from the condition by

providing worthwhile clinical improvement. LSDP Funding:

50

PBAC looks at the following issues in deeming a submission acceptable for LSDP funding , and in formulating a recommendation to the Minister: A drug must meet the following criteria: 1) The TGA has approved the drug and its indication for treatment

of a clinically definable rare disease. 2) The disease can be identified with reasonable diagnostic

precision.

PBAC (initial submission) — Yes LSDP – (PBAC rejected due to cost-effectiveness); Initial PBAC submission stands and only additional economic requirement for LSDP is to indicate if the drug has been previously rejected for PBS listing due to failing cost-effectiveness criteria.

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included in a submission to PBAC. However, it would be unlawful for PBAC not to consider comparative costs and effectiveness.”

48

The “rule of rescue” may be applied as a supplement to orphan drug submissions if the four delineated factors are present, however the rule does not replace consideration of evidence-based comparative cost-effectiveness. Submissions for rare diseases that: a. PBAC finds clinically

effective but ineligible for listing on the PBS due to cost-effectiveness issues, and

b. meet the eight LSDP-specified funding criteria, are referred to the LSDP for review and a decision on potential funding using a separate budget.

3) Age-specific life expectancy of affected patients is significantly reduced, as supported by epidemiological and other study evidence acceptable to PBAC.

4) PBAC acceptable evidence supports direct and substantial lifespan extension for patient’s treated with this drug.

5) PBAC accepted the clinical effectiveness, but rejected the cost-effectiveness criteria for listing this drug on the PBS Schedule.

6) No alternative life-saving drugs are available for hospital in-patients or listed on the PBS for treating this specific disease. (Note: Availability of an alternative drug for this condition under the LSDP does not preclude consideration of this drug as well.)

7) There are no suitable, recognized, cost-effective non-drug therapies available for this condition.

8) The annual cost of the drug would be considered an unreasonable financial burden for the patient or guardian. (Note: Annual cost defined as (cost/dose) x (expected # doses/ year/ patient)

51

PBAC also considers and provides advice in consideration of the following , if applicable: a. The proposed drug price is compared with the drug’s

effective price in comparable overseas markets. b. The proposed drug price is compared with any comparable

LSDP-funded drugs. There are also specific patient eligibility criteria for the drug as well as ongoing monitoring requirements that, once approved for therapy, 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 information found regarding a separate process

Not applicable Not applicable (HAS does not examine any economic evidence)

52

Germany (IQWIG) No publicly available

information found regarding a separate process.

Not applicable Yes

http://www.health.gov.au/lsdp

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Scotland (SMC) No, the assessment process is same as that for all other drug submissions; however, some “modifiers” are acceptable for orphan drugs (see details column).

Although all drug submissions are required to be comprehensive and complete, SMC may choose to be more flexible and allow acceptance of more uncertainty in the economic case or a higher cost per QALY for orphan drugs. SMC has no formal cost per QALY thresholds for demonstrating cost-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

Yes

UK (NICE/AGNSS)54

Effective April 2013, NICE is again responsible for coordinating the evaluation of expensive ultra-rare orphan drugs. An interim method that builds on the framework used by AGNSS has been developed for the evaluation of such highly specialized drugs. Before April 2013, (and since 2005), NICE referred assessments of ultra-orphan drugs to AGNSS, a specialized national commissioning body.

The evaluation of technologies by the “highly specialised technologies programme” engages a specific evaluation committee that is an independent advisory body. The committee, comprising individuals who work in the National Health Service, pharmaceutical and medical devices industries, patient and caregiver organizations, and relevant academic disciplines, makes recommendations to NICE for or against the use of a technology based on its costs and benefits. “Given the very small numbers of patients living with these very rare conditions a simple utilitarian approach, in which the greatest gain for the greatest number is valued highly, is unlikely to produce guidance which would recognize the particular circumstances of these very rare conditions. These circumstances include the vulnerability of very small patient groups with limited treatment options, the nature and extent of the evidence, and the challenge for manufacturers in making a

NICE (Highly specialised technologies programme) —Yes AGNSS — Yes

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AGNSS followed a specific decision-making framework for orphan drugs.

55

reasonable return on their research and development investment because of the very small population treated.”

56

The following criteria are taken into consideration during the evaluation:

nature of the condition (including morbidity/clinical disability with current standards of care; effect on caregivers’ quality of life; current treatment options)

impact of the new technology (clinical effectiveness; magnitude of health benefits for patients, and caregivers when appropriate)

cost to the National Health Service and Personal Social Services (including budget impact; robustness of costing and budget impact information; patient access agreements)

value for money (benefit compared to current treatment; other resources needed to use the technology; impact on budget available)

impact beyond direct health benefits (are there any such benefits, are costs/savings incurred outside of the NHS and PSS)

impact on delivery of the specialized service (staffing and infrastructure requirements such as training, planning for expertise).

56

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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best practice (best clinical practice; economic efficiency of provision; continuity of provisions; accessibility and geographic distribution balance).

57-59

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

For the same selected international HTA agencies as in the previous table (Table 4), Table 5 summarizes reimbursement decisions for the following DRDs:

Ivacaftor (Kalydeco) — for cystic fibrosis with G551D mutation Eculizumab (Soliris) — for paroxysmal nocturnal hemoglobinuria (PNH) Sapropterin (Kuvan) — for phenylketonuria Idursulfase (Elaprase) — for Hunter Syndrome (aka MPS II).

Table 5: International HTA Agency Reimbursement Decisions for Selected DRDs

Kalydeco (ivacaftor) Cystic fibrosis with G551D mutation

Soliris (eculizumab) PNH

Kuvan (sapropterin) Phenylketonuria

Elaprase (idursulfase) Hunter Syndrome (MPS II)

Canada

(CADTH CDR) March 22, 2013: Recommendation - to list only if both of the following conditions are met: “1. Substantial reduction in

price: ivacaftor will not be considered cost-effective without a substantial reduction in the submitted price

2. Clinical criteria for the discontinuation of ivacaftor treatment in patients who fail to demonstrate a meaningful response must be developed in consultation with CF treatment clinics.”

60

February 19, 2010: Recommendation — do not list at the submitted price. “Eculizumab would not be considered cost-effective without a substantial reduction in the submitted price.”

61

January 26, 2011: Recommendation — do not list. “Patient details were insufficient to identify a subpopulation for whom sapropterin may provide a significant clinical benefit that is cost-effective.”

62

December 19, 2007: Recommendation — do not list. “1. While idursulfase has been

shown to have a biologic effect and improve some outcomes in patients with Hunter syndrome, the clinical significance of

its effects is not established. 2. It is unlikely that idursulfase

enters the central nervous system and therefore, it is not

expected to improve the neurological complications of

Hunter syndrome.

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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 (PBAC, LSDP)

July 2013 PBAC agenda: requesting section 100 (Highly Specialised Drugs Program) listing or inclusion on the LSDP (decision not yet public).

64

July 2008: PBAC recommendation – application rejected due to “unacceptably high and highly uncertain estimated cost per additional death avoided over a 2-year period.” Also rejected application for LSDP consideration.

65

Effective May 10, 2010 - PBAC decision that Soliris for PNH met criteria for LSDP. Available through LSDP for treatment of PNH.

65

July 2012: PBAC recommendation was a deferral of the submission so that discussion could take place with the sponsor regarding price. Sponsor working with “PBAC and the Department to ensure timely access to Kuvan through the LSDP”.

66

No LSDP listing yet.

November 2007: PBAC rejected application on the basis of unacceptably high cost-effectiveness; however for treatment of MPS II, idursulfase meets criteria for the LSDP.

67

Available through LSDP for treatment of MPS II.

68

France (HAS) November 7, 2012: “The Transparency Committee recommends inclusion on the list of medicines refundable by National Health Insurance and on the list of medicines approved for hospital use in the indication “treatment of cystic fibrosis in 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

Not found in HAS database as reviewed for PNH indication. A Euro Observer article indicated that the appraisal outcome was “list with criteria.”

70

February 4, 2009: “The Transparency Committee recommends inclusion on the list of medicines approved for use by hospitals and various public services in the indication and at the dosage given in the marketing authorisation.”

71

Not found in HAS database as reviewed. A Euro Observer article indicated that the appraisal outcome was “list with criteria.”

70

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Germany (IQWIG) November 15, 2012: IQWIG indicated Kalydeco may breach the 50 million Euro per year cost threshold and may require an additional reimbursement evaluation.

72

Not in IQWIG database as reviewed Not in IQWIG database as reviewed

Not in IQWIG database as reviewed

Scotland (SMC) December 7, 2012: “Advice following a full submission: 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 measured 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 to gain acceptance by SMC and in addition the company did not present a sufficiently robust economic analysis to gain acceptance by SMC. The licence holder had indicated their intention to resubmit.”

73

October 8, 2010; amended July 11, 2011: “Advice following a full submission: eculizumab (Soliris) is not recommended for use within NHS Scotland. Indication under review: for the treatment of patients with PNH. Evidence of clinical benefit of eculizumab in the treatment of patients with PNH is limited to patients with a history of transfusions. In a controlled study in patients with transfusion-dependent PNH, eculizumab reduced the rate of haemolysis and improved anaemia compared to placebo. Uncontrolled data suggest that eculizumab reduces the incidence of thrombosis in patients with PNH. The manufacturer did not supply any health economic analysis and cost-effectiveness was not demonstrated in an independent economic analysis therefore eculizumab cannot be recommended for use within NHS Scotland.”

75,76

May 5, 2009: “Advice in the absence of a submission from the holder of the marketing authorisation sapropterin (Kuvan) is not recommended for use within NHS Scotland for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients with phenylketonuria (PKU) and for the treatment of hyperphenylalaninaemia (HPA) in adult and paediatric patients with tetrahydrobiopterin (BH4) deficiency. The holder of the marketing authorisation has not made a submission to SMC regarding this product in this indication. As a result we cannot recommend its use within NHS Scotland.”

77

July 6, 2007: “Advice following a full submission idursulfase (Elaprase) is not recommended for use within NHS Scotland for the long-term treatment of patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II). Idursulfase was approved by the EMA under exceptional circumstances and has been designated an orphan medicinal product. The manufacturer’s justification of the treatment’s cost in relation to its health benefits was not sufficient to gain acceptance by SMC and, in addition, they did not present a sufficiently robust economic analysis.”

78

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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 will be funded by the NHS in England for all patients aged 6 years and over with cystic fibrosis and the G551D gene mutation.” Kalydeco was reviewed by the Clinical Priorities Advisory Group (CPAG), which was established in September 2012 specifically for evaluation of this new drug, on behalf of the four Specialised

AGNSS - Not reviewed NICE – Not reviewed (Topic selection process between July 2006 and December 2008 wave 15-21: rejected prior to topic selection panel). Not referred to AGNSS. As an aside - Soliris for atypical hemolytic uremic syndrome (aHUS) indication: The positive recommendation for Soliris in aHUS

AGNSS – No information found; assuming not reviewed NICE – Not reviewed (Topic selection process between July 2006 and December 2008 wave 15-21: rejected post topic selection panel, pre-scoping)

83

AGNSS – No information found; assuming not reviewed NICE – Not reviewed (no record of consideration on NICE website)

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Commissioning Groups in England. The group adopted the decision-making framework used by AGNSS. The decision was based on a review of the drug’s clinical and cost-effectiveness.

79

made by AGNSS was rejected in January 2013 by the UK government and the reimbursement review has subsequently been referred to NICE. Review estimated to be completed 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-specific Evaluation Frameworks for Evaluating DRD Funding

a. Ontario’s DRD Evaluation Framework

The Ontario Ministry of Health and Long-Term Care developed a separate evaluation framework for assessing funding of DRDs under its publicly funded drug program. A framework was needed due to the absence of a national strategy for reviewing and evaluating rare disease drugs and because of a historic and ongoing need to address patient access to these drugs in Ontario.

84 This evaluation is

conducted by a separate five-member DRD Working Group, that has physician, economist, pharmacist, and geneticist representation and reports directly to the Executive Officer of the Ontario Public Drug Programs.

85 There are no restrictions on the types of

rare diseases considered for evaluation under this framework, and requests for funding consideration under the DRD framework may be submitted by manufacturers or physicians.

84

The evaluation framework uses an evidence-based process and considers the best achievable evidence for the particular drug under review, with indirect evidence taken into consideration when necessary. Predictive models identifying the natural progression of a disease, where a drug might provide the treatment effect, and the patients most likely to benefit from treatment, are used to inform the funding decisions.

85

The framework consists of five steps:

8,84,85

Step 1 – Assesses whether a submitted disease meets the framework’s criteria of “rare” Determination of whether a DRD is eligible for review under the framework is determined by: a) disease incidence rate of fewer than 1 in 150,000 live births or new diagnoses per year b) lack of availability or feasibility of adequately powered randomized controlled trials detecting clinically relevant outcomes, given the rarity of the disease. Step 2 – Gains an understanding of the natural history of the disease This step entails a review of the disease state itself, including its presentation, progression over time, underlying mechanism, and consequences, as background information for understanding the

mechanism(s) of action of the drug candidate under review.

8

Step 3 – Assesses the potential effectiveness of the drug, based on the best available evidence This step evaluates the clinical evidence supporting the drug candidate. This includes direct clinical trial data on the drug and indirect evidence (e.g., from other disease conditions) where appropriate. When only sparse or questionable clinical data are available, use of the Bradford Hill criteria for causality, adapted for treatment assessment, is applied as a tool in assessing whether the drug alone potentially caused the reported patient benefits or not.

86

Step 4 – Evaluates budget and cost impact Cost-effectiveness analyses are not conducted, nor is cost-effectiveness a deciding factor in evaluating a drug under review by this framework; however, the affordability of the product is taken into consideration in formulating the final decision. Step 5 – Identifies whether any additional follow-up data is needed This step identifies whether and what types of other studies may be required to generate more information. To date, Ontario’s DRD Evaluation Framework has been used for the evaluation of seven DRD submissions: five drugs indicated for genetic lysosomal storage disorder drugs, one drug for skin cancer, and one drug for a group of genetic auto-inflammatory diseases.

85 Compared with the time

taken to perform a regular drug review, Ontario’s experience has shown that DRD reviews take a longer time to complete. This can be attributed to the increased amount of time needed to comprehensively review the disease state and drug, as well as the time required to develop a predictive disease model.

87

b. Alberta’s Rare Diseases Drug Program

On April 1, 2009, Alberta launched a Rare Disease Drug Program for eligible Albertans under its publicly funded drug plan. This program was developed for ethical and compassionate reasons to help affected individuals with the exceptionally high costs of rare disease drugs.

88 For the purposes of this program, a

rare disease is defined as a genetic lysosomal storage disorder occurring in fewer than 1 in

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50,000 Canadians, as determined by Alberta Health.7

Thus this program reviews requests only for the specified lysosomal storage disease category of rare diseases, which includes, for example, Fabry disease, Pompe disease, and Gaucher disease. Submitted applications are reviewed by Alberta’s Rare Disease Clinical Review Panel, which is a Ministry-appointed panel consisting of rare-disease-treating specialists and other health care professionals with related clinical expertise. Rare Disease Drug Coverage Applications can be submitted for an individual patient by their “rare disease specialist,” as defined by each drug’s eligibility criteria. When applying for coverage of a rare disease drug, applicants must consent to a number of conditions should coverage be approved. These conditions are as follows: a) Conditional initial and continued coverage are dependent upon clinical outcomes. b) Ongoing clinical outcome monitoring is mandatory. c) Inadequate patient response or deterioration, as defined by pre-established withdrawal criteria for a specific drug and/or as assessed by the program’s clinical review panel, will dictate coverage discontinuation. Note that the presence of a significant illness likely to affect life expectancy, outside of the rare disease itself, is considered a contraindication to the rare disease funding.

7

Final coverage decisions for rare disease drug funding are made by Alberta’s Minister of Health, and the Minister “may list a drug product under this section when the Minister considers it in the public interest to do so.”

7

c. Alberta’s Short Term Exceptional Drug Therapy

(STEDT)

In addition, On March 1, 2012, Alberta’s provincial government announced a new Short Term Exceptional Drug Therapy (STEDT) program that allows funding consideration for certain therapies without current public or private funding options.

89,90

Specialist physicians can submit requests to fund high-cost non-formulary drugs for rare conditions for in-patients whose drug therapy (oncology drugs

included) costs are expected to be between $1,500 and $50,000. Outpatients’ applications for drugs used to treat rare clinical conditions (excluding oncology indications) are eligible for assessment if the total drug cost is expected to be less than $100,000 per year. Specific funding criteria are used to objectively review requests on a case-by-case basis. If approved, funding is provided for an agreed upon duration beyond which resubmission would be required. The request form, to be completed by a specialist physician working at an Alberta Health Services facility and actively treating a patient for a rare clinical condition, requires the provision of the following information: details about the requested drug (indication,

dose, frequency, duration of therapy, costs) whether any alternative therapies exist, have

been tried, or ruled out providing evidence that supports use of the drug

for the requested indication details about objective measurable clinical

outcomes and when they would be expected to occur

information about discrete indicators of treatment failure and that therapy should be discontinued.

91

Specific details regarding funding criteria or decision-making frameworks for Alberta’s Rare Disease Drug Program or STEDT could not be found in publicly available information.

d. British Columbia’s Program for DRD Funding Evaluation

No publicly available information was found regarding British Columbia’s public drug plan’s DRD funding evaluation framework.

Summary

DRD Regulatory Trends for Key Regulators

US Since the institution of the 1983 US FDA Orphan Drug Act, the number of orphan drug designations and approvals between 1984 and 2010 remained generally constant, with an average of 10 per year; however, as the total number of US drug approvals has been declining since the peak in the 1990s, the proportion of new drug approvals attributed to

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orphan drugs has risen from 17% in the 1990s to over 35% between 2008 and 2010, a trend that is expected to continue. The majority of approvals have been for oncology drugs. It is estimated that 15.5% of US orphan drug designations made since 1983 have been approved.

European Union Since the start of the EU Orphan Regulation in 2000 until 2012, the number of orphan drug designations by the EC has risen steadily. Almost 1,100 designations have been granted, starting with 14 in the first year to 148 in 2012, with the majority of designations being for oncology drugs. An estimated 7% of all orphan drug designations granted since 2000 have received centralized marketing authorization for the EU. Canada Until October 2012, Canada had no policies and no regulatory framework for orphan drugs. Currently, there is a Health Canada draft discussion document for an orphan drug regulatory framework that would define an orphan drug as one that meets certain criteria including disease prevalence and disease severity. Sponsors of orphan drugs would submit applications for orphan drug designation to Health Canada. If granted, sponsors would be eligible for specified regulatory incentives.

Biopharmaceutical Industry Pipeline for DRD

The DRD pipeline is rapidly evolving, and grows almost daily. In 2012, worldwide orphan drug sales totalled $83 billion representing approximately 13% of the worldwide prescription sales (excluding generics). This is expected to rise to 15.9% by 2018

and would represent an estimated $127 billion in sales.

Health Technology Assessment Reimbursement Frameworks for DRD

Of the six selected HTA organizations scanned for publicly available information, only one (NICE) has a DRD-specific evaluation framework. Most agencies (CDR at CADTH, PBAC and LSDP in Australia, and SMC in Scotland) currently evaluate DRDs through their standard processes, with some allowing for more flexibility in their cost-effectiveness thresholds when evaluating DRDs. The Ontario Ministry of Health and Long-Term Care has a well–developed separate evaluation framework specific to DRDs. Using an evidence-based process, the decision-making framework considers the best achievable evidence for the drug under review, taking indirect evidence into consideration when necessary. Predictive models help inform funding decisions by identifying the natural progression of a disease, where a drug may provide the treatment effect, and the patients most likely to benefit from treatment. Alberta has a Rare Disease Drug program, which 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 Drug Therapy program for funding high-cost non-formulary drugs for rare conditions is available for both in-patients and outpatients. British Columbia’s public drug plan has a DRD framework, but no publicly available information was found.

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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) Alexion

PNH $409,500

Elaprase (idursulfase) Shire

Hunter syndrome $375,000

Naglazyme (galsulfase) BioMarin

Maroteaux-Lamy syndrome (MPS VI) $365,000

Cinryze (C1 esterase inhibitor, human) ViroPharma

Hereditary angioedema $350,000

Myozyme (alglucosidase alfa) Genzyme

Pompe disease $300,000

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 1983 (and 1984, 1985, 1988, 1992 amendments)

The drug (expanded to include biologics, medical devices, medical foods) is indicated for treatment, diagnosis, or prevention of a disease or condition affecting fewer than 200,000 people in the US at the time of the orphan drug designation submission; or affects more than 200,000 people in the US but costs of developing the drug and making it available in the US not expected to be offset by US sales of the drug in the first seven years.

A product must not have been previously approved for the disease/condition for 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

1. Clinical research protocol assistance

2. Seven (7) years of market exclusivity beginning at the date of FDA approval for the designated orphan indication

3. Availability of research grants

4. 50% tax credits for clinical research costs

5. Waiving of new drug application filing fees

6. Can apply for accelerated review (not specific to orphan drugs)

22,95

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EMA

The Orphan Regulation 1999 – (EC) No 141/2000 (and (EC) No 847/2000)

Only medicinal products for human use can apply for orphan drug designation (no medical devices, nutritional supplements, or dietary products).

“Must be intended for the treatment, prevention, or diagnosis of a disease that is life-threatening or chronically debilitating.

The prevalence of the condition in the EU must not be greater than 5 in 10,000, or it must be unlikely that marketing the medicine would generate sufficient returns to justify the investment needed for its development.

No satisfactory method of diagnosis, prevention, or treatment of the condition concerned can be authorized, or, if such a method exists, the medicine must be of significant benefit [defined as a clinically relevant advantage or a major contribution to patient care]

96 to those

affected by the condition.”2

A new indication for an already authorized product is eligible for orphan designation application.

Orphan designation can be granted to multiple sponsors for the same product indicated for the same disease or condition.

Regarding marketing exclusivity:

Once marketing authorization is granted to an orphan product, another application for marketing authorization 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

1. Protocol assistance at a reduced charge – scientific advice from the Agency specifically for orphan medicines regarding types of studies needed to support a medicine’s quality, benefits, and risks, and information on significant benefit of the medicine

2. Access to the centralized authorization procedure for the EU (single application to EMA, resulting in single opinion and decision from EC which is valid in all EU member states).

3. Ten (10) years of market exclusivity (extended by 2 years for medicines that also comply with required pediatric investigations)

4. Fee reductions for regulatory activities – including protocol assistance, marketing authorization applications, inspections before authorization, applications for changes to market authorizations made after approval, reduced annual fees.

5. Additional incentives for micro, small, and medium-sized enterprises – including administrative and procedural assistance, and fee reductions

6. Can apply for accelerated review (not specific to orphan drugs)

7. Potential for incentives/grants by member states or EC

96,97

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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 Provisions

US (FDA) EU (EMA) Australia (TGA) Japan (MHLW)

Orphan Drug Legislation/Policy

Orphan Drug Act 1983

Orphan Regulation 1999 – (EC) No 141/2000

Orphan Drug Program 1997

Orphan Drug Regulation 1993

Marketing Exclusivity Period

7 years 10 years (extended by 2 years for medicines that also comply with required pediatric investigations)

5 years 10 years

Accelerated Evaluation Availability

Yes Yes Yes Yes

Application or Other Regulatory Fee Reductions or Waivers

Yes Yes Yes No

Scientific Advice (Research Protocols, Technical Assistance, etc.)

Yes Yes Yes Yes

Tax Incentives 50% tax credits for clinical research costs

Tax credits developed by each member state

No Tax Exemption Law (12% of expenses)

Other Clinical research funding through Orphan Products Grants Program

Access to EU centralized authorization process Additional incentives for micro, small, and medium-sized enterprises – including administrative and procedural assistance, and fee reductions

Extension of registration validity period Development costs partially reimbursed

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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Environmental Scan


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Environmental Scan


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Environmental Scan


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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.

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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.

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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 and ... · Drugs for Rare Diseases: Evolving Trends in Regulatory and Health Technology Assessment Perspectives Author: Canadian