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Orphan Drug status
Is it sustainable?
20 février 2014
1
Disclaimer
This is an independent study performed by
students from Faculté des Sciences
Pharmaceutiques de Lille.
The opinions expressed are our own.
2
Orphan drug prices :Hot topic in the press
Million-dollar therapy will test payers' tolerance of orphan drug prices
Fierce BiotechJanuary 2013
Drug Makers See Profit in Rare Diseases
Wall Street Journal January 30, 2013
NPS Pharma: Controversy Over Super-Expensive Orphan Drug Prices
TheStreet.com January 2013
Tiger in the Fiscal Room: Beware the Increasing Cost And Number of Orphan Drugs
Managed Care Magazine March 2013
Inside The Pricing Of A $300,000-A-Year
Drug
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Inside the pricing of A $300,000-A-Year Drug:
GATTEX
Approved in 2012 and indicated to treat the Short Bowel
Syndrome.
Short Bowel Syndrome:
Malabsorption disorder caused by surgical resection of small
intestine (lenght < 2m), resulting from: Crohn’s disease,Tumors,
Necrotizing entorocolitis, Injury or Trauma…
Leads to malabsoprtion of proteins,
nutrients, fluids and electrolytes.
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Inside the pricing of A $300,000-A-Year Drug:
GATTEX
Symptoms:
• Fluid imbalance
• Weight loss
• Anemia
• Malnutrition
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Inside the pricing of A $300,000-A-Year Drug:
GATTEX
•
Intestinal adaptation:
Remaining portion of the small intestine may increase its
absorptive capacity.
Normal
Nutrient layer mobility
Adapted
Villi
Blood flow
6
Inside the pricing of A $300,000-A-Year Drug:
GATTEX
Treatments:
Depending on severity, malabsorption can be overcome by: increasing oral
uptake…
But…If this treatment fails, patients become dependant on PN/IV
Nutrition.
Inherent risks
Catheter infection=100%
Diarrhea=50%
Ostomy leak= 38%
Impact :
Change ostomy bag 3-4X a day
2-3L watery diarrhea a day
On PN/IV 10 hrs up to 7 days a week
Sleep is disrupted
Can’t work
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Inside the pricing of A $300,000-A-Year Drug :
GATTEX
GLP2 Like Peptide 2 recombinant analogue, delivered daily by subcutaneous inj.
•
Suppresing gastric acid secretion
and gastric motility
•
Stimulating intestinal nutrient transport
•
Intestinal blood flow and crypt cell
proliferation
•
Increases villus height
 Gattex enables to reduce PN/IV dependence
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Clinical trials
• STEPS STUDY
• Primary Endpoint: PN/IV Volume reduction≥20%
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Clinical trials
• Secondary endpoint: Additional day off
gained
n=21
n=9
n=8
n=3
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How do they justify the price?
 Small population
At first…15000 eligible patients (expected to charge
$100000/year) based on 3 prevalence studies
But…the results looked very different, roughly 1000
patients.
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How do
How
dothey
theyjustify
justifythe
theprice?
price?
Costs direct &
indirect
PN/IV
$185,000-$578,000 a year
including:
Gattex
$295,000
-Fluid and supplies:
$75000-$122,000
- Home services:
$100,000-$250,000
- Hospitalization costs: $10000196,000
-Fluid and supplies:
$130,000
Example: Primary endpoint: 30% reduction in fluid volume of PN
Gattex: 295,000$
+
Fluids and supplies: $91000
+
Home services: $100,000-$250,000
+
Hospitalization costs: $10000-$196000
------------------------------------------------------$386,000 + ($110,000 – $444,000)
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How do
How
dothey
theyjustify
justifythe
theprice?
price?
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How
do
they
justify
the
price?
How do they justify the price?
 Perceveid level of unmet medical need
85% of patients are covered
Coverage and co-pay assistance program established by NPS
 Payers are willing to pay: burden of illness, clinical value, small number of14
patients…
Pricing issues?
Pricing issues?
• Elelyso: Gaucher’s disease $355,800
•Kalydeco: Cystic fibrosis
$311,500
•Juxtapid: Homozygous familial hyperchol. $ 295,000
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Historic overview
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History
KefauverHarris
Amendement
1962
Drug
coalition
 NORD
Orphan
Drug Act
70’s
1983
US
1993
Orphan
Drug Act
in Japan
2000
Orphan
Drug Act
in Europe
Others
• In Europe and US: 55 million people suffering from rare
disease.
• 5000-7000 rare diseases exist in the World.
• 250 new diseases described every year.
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Procedure of Designation
EMA
COMP
European
Commission
•
The submission is free of charge
•
Designation as an orphan medicinal product does not indicate that the product
has already satisfied the efficacy safety criteria necessary for the granting of a
marketing authorization.
•
Information for the submission
 Rare disease description
 Active Substance description
 Discussion on the rationality of using this molecule in that rare disease.
 Almost 70% of positive response for designations.
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Criteria for designations
EUROPE
US STATES
UNITED
Prevalence < 5 / 10 000
Prevalence <200 000 in the US
Or
Insufficient return on investment
Or
Insufficient return on investment
And
No satisfactory method
Or
Significant benefit
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Incentives
EUROPE
UNITED STATES
Protocol assistance
Protocol assistance
Access to the centralized
authorization procedure
Tax credits of up to 50% of R&D
costs
EMA fee reductions
FDA fee waivers
Additional incentives for Small
&Medium entreprises
Research grants
10 years of market exclusivity
7 years of market exclusivity
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Orphan Drug Regulatory Process in EU
Fee
Reduction
Submission
for
designation
Designation
Centralized
Procedure
Submission
for Marketing
Authorization
MA
10 years of
market
exclusivity
Protocole
assistance
Clinical development
Drug
Discovery
Molecule
Identification
Pre-clinical
test
Phase 4
Phase 1 Phase 2
Phase 3
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Designations : US, EU, JAPAN
In 2007 : FDA&EMA adopt common Orphan Drug designation Application form
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Source : EvaluatePharma®
Designations and Approbations in Europe
120
100
80
60
Designations
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For 10 years :
- 829 designations
- 63 Marketing
Authorizations
Marketing
authorizations
20
0
180
Year
Number of positive opinion
Number of orphan designations and
marketing authorizations
140
161
160
140
120
100
78
80
60
35
40
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8
20
0
0-1
1-2
2-3
3-4
Prevalence (per 10,000)
4-5
Nature reviews : European regulation on orphan medicinal products : 10 years of experience and future perspectives
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Top 15 companies
14
WW Orphan prescription sales ($bn)
12
10
8
6
2012
2018
4
2
0
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Source : EvaluatePharma®
Orphans marketing authorization by therapeutic
area in Europe
Oncology
Alimentary tract and
metabolism
1% 1%
8%
4%
Haematology
11%
44%
Respiratory and cardiovascular
11%
Nervous system
20%
Immunology
Hormonal
Distribution of orphan drug
marketing authorizations by
therapeutic area
Other
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Nature reviews : European regulation on orphan medicinal products : 10 years of experience and future perspectives
An other distribution of orphan drugs
Rare diseases treatment can be regrouped in 4 categories in Europe:
• Orphan Oncology drugs
– 44% of ODs approved
• Orphan non Oncology drugs
– Repurposed Drugs : 10% of ODs approved
– Second to market rare disease :16% of ODs approved
– First to market rare disease : 30% of ODs approved
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Eventually
a
mistaken
view
Eventually a mistaken view
Comparison of the top 5 european countries’ mean treatments for ODs and mean price
treatments for a sample of non-rare disease hospital drugs.
€250,000
Top 5 EU countries Mean Price
€200,000
€200,000
€150,000
€100,000
€50,000
€24,019
€16,000
€31,159
€24,716
€13,000
€0
1st to market ( non 2nd to market (non Repurposed drugs (
oncology)
oncology)
non oncology)
30%
16%
10%
Oncology
Rheumatoid Arthritis Other Non orphans (
Cancers…)
44%
Orphanet Journal of Rare Diseases 2013: Sustainable rare diseases business and drug access: no time for misconceptions
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Misconceptions
Comparison of the performance of specialized orphan drug
companies with other companies
Average %
100
90
Specialized orphan drugs companies
80
Large pharmaceutical companies
70
Medium-sized pharmaceutical companies
Small pharmaceutical companies
60
Biotechnology companies
50
40
30
20
10
0
Gross margin
R&D as percentage of sales
EBITDA margin
ROE ( accounting)
ROE (market capitalization)
Pure orphan players have not been performing as strongly as perceived.
Nature: Are orphan drug companies the pick of the pharmaceutical industry?
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2000-2020:
Sales
Growth
in
Europe
Growth forecast
29
Orphanet journal of rare disease : estimating budget impact of orphan medicines in Europe : 2000-2020
Outside the framework
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Trisenox® by CellTherapeutics
• Arsenic Trioxide
• Injectable formulation
• Approved in 2000 by the FDA, Cell Therapeutics, Seattle
• Treatment of an orphan disease : acute promyelocytic
leukemia (APL) :
• 2nd intention : Patients with refractory to, or have
relapsed from retinoid and anthracycline chemotherapy
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Trisenox® by Cell Therapeutics
• APL :
• About 2000 patients in the USA
• Treatment :
• Trans retinoic acid
• Antracycline based chemotherapy
• 2nd line : arsenic trioxide
• Bone marrow transplant
• Clinical trials of Trisenox :
• The drug was shown to be effective with 87% of the
patients achieving complete remission
• At a mediane of 57 days of treatment
• SMR : Important
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Trisenox by Cell Therapeutics
• 22,000 $ for a year of treatment
• Concerns about 400 patients in the USA
• Designated Orphan Drug :
• Financial breaks by the federal government
• Market exclusivity for 7 years
• In the USA :
• Marketing off label prohibited
• BUT drug’s reach not limited to its approved use
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From 502,000 $ to…
$ 502,000
4th quarter 2000 : 1st quarter on the market
•Trisenox has a potential whole host of blood cell-related
cancers : multiple myeloma : 15 000 new cases a year
• Medicare agreed to reimburse for off-label prescriptions in
16 states
$ 6,635,280
4th quarter 2001
Source: U.S. Department of Justice
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…to $ 27,635,280…
•
Wining the doctors :
• Conferences and dinners greeted by CTI sales and
marketing personnel to present informations about
Trisenox®
•
In 2003, only 10% of the prescriptions for the indication of
APL
Source: Cell Therapeutics
$ 27,635,280
2nd quarter 2003
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…to $ 81,335,280
Summer 2005 : CTI sold Trisenox to Cephalon
$ 81,335,280
4th quarter 2005
36
Cell Therapeutics fortunes turned…
• Lawsuit against the company accusing it
of illegally promoting Trisenox off-label
• The federal government joined the suit
• CTI accept to pay$ 10,5 million to resolve the allegations
• To this day, Trisenox has not been licensed for anything but the
rare disease that first put it on the market.
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Others federal alegations for promoting orphan
drugs for off-label uses :
Other drug makers accused of improperly promoting or
marketing orphan drugs licensed for rare diseases :
• Aranesp, Amgen :
✔ Anemia in patients with non-myeloid malignancies where
anemias due to the effect of concomitantly administered
chemotherapy
✘ Not approved : use of treating anemia in cancerous patients
who are not undergoing chemotherapy.
➜ $ 762 million to pay
• Temodal, Schering-Plough :
✔ Glioblastoma
✘ Otherforms of brain tumors and metastatic cancers
➜ $ 435 million to pay
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Strategies for repositioning orphan drugs
Finding new indications for existing drugs:
• Well known safety and pharmacocinetic profils
• Shorter development time and lower development costs :
• In vitro and in vivo screening
• Chemical optimization
• Toxicology
• Bulk manufacturing
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Strategies for repositioning orphan drugs
Effective against several orphan diseases
Different
strategies
Rare disease in a country can be a common
one in an other
From a rare disease into a common one
From a common disease into a rare one
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Different
strategies
(1/4)
Strategies for repositioning orphan drugs
Drugs effective against multiple rare diseases
Imatinib : approved for several orphan indications
•
Inhibiting on multiple tyrosine kinase :
• Chronic myeloid leukemia
• Acute lymphoblastic leukemia
• Aggressive systemic mastocytosis
• Gastro intestinal stromal tumors
• Hypereosinophilic syndrome
•
Increasing of the price :
• 2001 : $ 30,000
• 2012 : $ 76,000
In 2012 : sales are $ 4,7 billion
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Different
strategies
(2/4)
Strategies for repositioning orphan drugs
A rare disease in a country can be a common
one in an other :
Tropical diseases : Orphandrugs in the USA
• Antimalarials : Halofantrine and Mefloquine
• Leprosy : Thalidomide used for treatment of erythema
nodosum
• Antitubercular agents : Rifampin
42
Different
strategies
(3/4)
Strategies for repositioning orphan drugs
Rare into common disease
Bosentan, Actelion Pharmaceuticals :
Dual endothelin receptor antagonist
• Orphan approval:
• Treatment of pulmonary arterial hypertension
• Clinical trials in patients with chronic heart failure :
• Phase III, ENABLE
⇒ Not statistical significance for the risk reduction in time
to death or hospitalization, and clinical status
• Clinical trials in patients poorly controlled asthma :
• On going
43
Different
strategies
(4/4)
Strategies for repositioning orphan drugs
Common into rare disease
Sildenafil :
• Inhibiting cGMP Phosphodiesterase 5
• 1998 : Firstly approved for erectile dysfunction
• 2005 : Approved for the treatment of pulmonary
arterial hypertension
• Increase 6 fold the price compared to the common
posology
44
Reimbursement decision-making
Development of the AGNSS in UK: Advisory Group for National Specialised
Services.
1/ Rarity implies small patient populations
• High prices to recoup R&D
• Quality of the evidence
•  High and uncertain cost-effectiveness
2/ Special status of Orphan drugs
• Principe of equity
• Opportunity costs
•  Societal issue
45
Decision
methods
Other criterion
Criteria other than Cost-effectiveness are used for reimbursement.
Δ Cost = ICER < Willingness to Pay
Δ Effect
46
Decision
methods
Other criterion
Clinical benefit
Ethical/moral considerations :
• Equitable access
• Cost to patient if not reimbursed
Severity of the disease, Unmet medical need
Availability of other therapies
47
Decision
methods
Other criterion
Patients with rare conditions deserve the same quality, safety and
efficacy in medicinal products as other patients…” ( EU regulation).
Need for more quality clinical evidence:
Regulators and payers could more consistently appraise
orphan drugs Risks and Benefits.
48
Conclusion
• In 2011 : Only 15 % of Orphan drug among the NME
• In 2012 : 38% of NME
• In 2013 : 33% of NME.
• More data generation before and after the marketing authorization for
payers and agencies.
• A regular reassessment of the Ods in order to ensure an optimal use.
49
According to us
• For public, Orphan drugs seem to be a good way of making money
- Only 30% on Orphan Drugs are concerned by high prices.
- Moreover, development of that drugs tend to stabilize.
• Would orphan drugs brake the development of new drugs for common
diseases?
• Carry on incentives to promote orphan drug development.
50
Thank you for listening
Any questions?
51