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Orphan drugs
• Definitions
• Legislation
• Prevalence and evolution
Orphan drugs • Slicing
Doctoral seminar (9-10-2008) • Cost
Thomas De Rijdt, PharmD
• Dispensing
• Raw materials
• Rare diseases: capita selecta
• Conclusions
1
09/10/2008
Procedure EMEA/COMP
Legislation: orphan drug status • EMEA protocol assistance
• Europe : EMEA – COMP • Start at day 1
– Committee on orphan medicinal products • Study by COMP
– Since 2000 (Verordening
(V d i (EG) 141/2000 dd 16-12-1999)
16 12 1999)
• Advice COMP at dayy 90
– Incentives to encourage companies • Advice tot EC
• Protocol assistance • Conclusion of EC
• Financial benefits (fee reduction) – Within 30 days
• Marketing exclusivity (10 years) • Publication
• European registration (all countries) – A new orphan drug is born
– Not yet authorised for marketing for desired
indication (other procedure)
5%
7%
5%
3%5%
2%
5% 27%
30%
33%
34% 33%
38%
44% 42%
3%
2%
40% 5%
42% 4%
2%2% 3%
4%
7% 5%
5%
8% 5% 3%
5% 3% 5%
8% 8% 6%
6% 6%
Enzyme
Enzyme Antithrombotic
Antithrombotic Cardiac
Cardiac Antihypertensive
Antihypertensive Urologic Hypothalamic
Urological Antineoplastic
Hypothalamic Analgesic
Antineoplastic Other
Analgesic
AntineoplasticEnzyme Enzyme
Immunosuppressive
Antithrombotic Analgesic
Antithrombotic Antiepileptica
CardiacAntihypertensive
Antihypertensive Other Antineoplastic
Hypothalamic
Hypothalamic Antineoplastic
2
09/10/2008
4.0
3.5
49% 51% 3.0
2.5
2.0
1.5
1.0
0.5
Oraal 0.0
Parenteraal
3
09/10/2008
• Hydroxycarbamide
• Definition of ultra-orphan drugs
– =Hydrea (€ 0.1975 / 500 mg)
– Prevalence less than 0.18 / 10,000
– =Siklos (€ 600 / month) Orphan drugs and the NHS: should we value rarity
(McCabe, BMJ 2005;331:1016-1019)
4
09/10/2008
IPLEX(TM) is a complex
recombinant human insulin-like
growth factor-I (rhIGF-I) and its
predominant binding protein
IGFBP-3 (rhIGFBP-3).
Legislation
Raw materials
• Royal Decree 19-12-1997
• Orphan drugs regulated by EMEA
– Pharmacist has to use licensed materials
• If producing them is not lucrative • Magistral versus officinal preparations
– Not available as orphan
p drug
g • Certificate of analysis
– Not available as pharmaceutical grade – Update 2008 (to be published)
– Can be available as chemical grade • Better quality assurance by distributor
primary material • Magistral preparations only with licensed
– “Orphan raw materials” materials
– Request to adapt the RD
• A problem in tertiary care hospitals
• Use of orphan raw materials in hospitals
5
09/10/2008
Jaeken et al., A J Hum Genet 62 (1998), pp. 1535–1539 • Soon available: www.weesziektencentrale.be
Pompe disease
• First described by Johann Pompe in 1932.
• Infantile, or early onset
– Noticed shortly after birth
– Symptoms: severe lack of muscle tone, weakness, enlarged liver and heart.
Mental function is not affected. Development normal for the first weeks or
months but slowly declines.
declines
– Most children die before age of 2 years by respiratory / cardiac complication.
6
09/10/2008
Pompe disease
• Therapy
– Alfa-glucosidase
• Recombinant human enzyme
• Replaces the missing enzyme
• Breaks down glycogen.
– Prolongs ventilator-free
ventilator free survival and overall survival
– Studied by Genzyme
– Now commercial available as Myozyme
• Arterial hypertension
y
– Vasoconstriction
– Right ventricle enlargment (pumping)
– Heart failure and long fibrosis
• Venous hypertension
– Left hearth failure Æ pooling blood in lungs
– Treatment : diuretic, betablocker, ace-inhibitor,
valvesurgery
7
09/10/2008
Parkinson
• Duodopa (Belgium)
– Need steady level of dopamine
– When regular treatment fails
• Severe parkinson,
parkinson on-off
on off fluctuations
• Swith oral Æ intestinal administration
– Variability plasma level : 38 Æ 17 %
– Levodopa and carbidopa in intestinal gel
– Administration by pump
•Very expensive therapy
– Stability 15 weeks in fridge; 16 h at 40°C
•Surviving until surgery – € 45,000 / year / patient
•Partially financed by BSF (limited resources / budget)
8
09/10/2008
Reflections
Conclusions
• Orphan drugs have a special status
• Orphan drugs – Prevalence, profit, availability, legislation, …
– Definition depends on continent
– Need depends on population • Similar ?
– Status versus needs (eg raw materials) – Compassionate use
– Mostly very expensive therapies – Medical need
– Mostly live saving for a small population – Conventions
– Pharmacist has an important role – Clinical trial
• Advising, preparing, dispensing, reimbursement
– Off label use (especially in pediatrics, …)
– EMEA is supporting • “Drug orphans” versus “Orphan drugs”
– Ethical discussions are possible
BEROMUN
CEREZYME
fl 1000E
fl IV 1 mg
Imiglucerase
Baxter Hyland
Boehringer Ingelheim
nv
Genzyme nv
02/650.18.86
087/31.50.05
02/714.17.10
02/650.18.55
087/31.21.97
02/714.17.09
Ja
Ja
Ja
Thank you for
CYSTAGON caps 50 mg Mercaptamine Orphan Europe 02/461.01.36 02/461.02.36 Ja
CYSTAGON
ORLAAM
QUADRAMET
VITRAVENE
caps 150 mg
10 mg / ml
9
Orphan drugs
D
Dooccttoorraall sseem
miinnaarr
0099--1100--22000088
Thomas De Rijdt
UZ Leuven – Ziekenhuisapotheek
Summary : Since medicine and diagnostics have been improved over the years it now is
possible to detect more rare diseases, commonly known as “orphan diseases”. Patients
with these diseases are treated with “orphan drugs” and as there is, by definition, no
commercial benefit in producing this medication it is very expensive to buy on the market
or even very scarse to find in a non-pharmaceutical quality of the raw material for use in
compounding. Nevertheless, in large tertiary care centres these drugs are requested nearly
daily.
As there’s specific legislation for production and registration of orphan drugs and as these
medication package is taking a large amount of money from the national healthcare budget
In this presentation we’ll focus on the definition by EMEA, specific legislation concerning
Thomas De Rijdt
Definition
Some diseases are overlooked by doctors (for example Fabry’s disease, alveolar
echinococcosis, variant renal cancer, high myopia and even common conditions as
endometrial cancer and tobacco addiction) and are therefore described as orphan diseases.
However, the therm “orphan disease” is more specially used to designate diseases that
The definition of orphan diseases depends on the country. In the US orphan diseases have a
prevalence less than 1/200,000 Americans. In Japan prevalence has to be less than 1/50,000
while in Europe it has to be less than 5/10,000 and in Australia 1/2,000 citizens is the limit.
Most of these diseases have not been “adopted” by the pharmaceutical industy because they
provide little financial incentive for the private sector to make and market new medications
to treat or prevent them. Since 25 years different organizations like NORD (National
organization of rare diseases), NIH (National institute of health), Orphanet and Eurordis
(European organization of rare diseases) are listing up data. There are already 5,000 – 8,000
known rare disorders affecting 6 – 8 % of the population. For Europe we’re talking about
25 million patients(2).
European Union at the time of submission of the designation application at the European
cover the investment in development without any incentive and if no such method already
exists and the products will be of significant benefit to the patients are designated as an
orphan medicinal product(3). Similar, the Food and Drug Administration (FDA) defined that
orphan drugs refer to products that treats rare diseases affecting fewer than 1 in 200,000
Americans(4).
As mentioned in the doctoral school program “From target tot market” in the development
of new drugs only few molecules make it to the market. Most of the unlucky molecules
become shelf drugs and will be forgotten in time. Sometimes they can live a second life as
recreational drug or orphan drug. Other orphan drugs are intentionally designed to treat a
rare disease.
Legislation
To encourage the pharmaceutical sector to market these products in January 1983 the US
government installed the Orphan Drug Act (ODA) which gives tax reductions and an
extend marketing exclusivity of 7 years to the companies. This act augmented the number
of authorized orphan drugs enormously(5). It took until the year 2000 before the European
Medicine Agency founded its committee on orphan medicinal product (COMP) and created
they provide in protocol assistance, fee reductions, 10 year marketing exclusivity and central
European registration(6). Once the protocol is filed it takes maximum 120 days before the
European community refuses or publishes the status of orphan drug. From then the
During time there’s been an evolution in therapeutic category of the authorized orphan
drugs. In 2001 – 2003 the majority of the molecules were enzymes and were used for the
treatment of metabolic diseases (42 %), followed by the category of antineoplastic drugs (34
%). Time shifted these numbers in the advantage of antineoplastic drugs while other smaller
groups made their entry. In 2001-2007 the situation was charactersized by antineoplastics
42 % and enzymes 27 %. In 2006 the American top 5 of drugs used in the treatment of rare
diseases showed similar rankings: cancer (38 %), metabolic diseases (37 %), infectious
diseases (23 %), neurologic disorders (18 %) and hematological disorders (16 %)(5).
Cost
As companies are encouraged to market drugs for the treatment of rare diseases it is
theoretically possible to slice a disease until the subtypes have a prevalence of less than 5 in
10,000 to benefit from the specified incentives. In the US chloretazine and oxaliplatin are
recognized as orphan drugs for treatment of leukemia (divided into 18 types)(7), in Europe
we find Glivec, Tasigna and Sprycel for treatment of chronic myeloid leukemia (CML).
The development of orphan drug isn’t rocket science but nevertheless it needs special
attention. Because of the small population research has to be organized international and
shows often more case reports than fully randomized clinical trials. Some products are
Because of their orphan drug status these products are often given high vending prices (eg
therapy costs. A patient suffering from mucopolysccharidosis and treated with Aldurazyme
costs about € 300,000 / year to the community. In Belgium are 12 known patients. Such
amounts and numbers can be cited for all rare diseases. This huge impact on the budget for
such a little group of patients can lead to ethical discussions. In the Maastricht Treaty of
December 1991 EMEA stated that every citizen has the right to receive all proper needed
Nitisinone once was a low cost herbicide. Since it is used for treatment of tyrosinemea it
achieved a orphan drug status and is marketed as Orfadin at the price of € 58 per tablet.
This makes it 400 times more expensive than solid gold. An analog story can be told for
Siklos and Wilzin. Nevertheless this medication is sold a high prices manufacturers are not
always taking best care of packaging. This drugs are distributed in bottles in stead of high
There’s an important role for the pharmacist in dispensing orphan drugs. For the most
recent drugs the government demanded companies to set up a risk management program
(eg Revlimid, Thalidomide). Applying this program takes time and skills of the pharmacists
while they’re not paid for this work. Only € 7,11 is provided for covering the costs of
Raw materials
available as pharmaceutical while they’re needed to threat patients. Especially tertiary care
hospitals are dealing with this problem. Most of these molecules are available as raw
material in chemical or HPLC grade. The Royal Decree of 19-12-1997 stipulates that a
pharmacist can use non licensed materials for magistral compounding if they are analysed by
a certified laboratory. In the 2008 adaptation of the RD this will not be allowed anymore.
the conditions in which a pharmacist is permitted to use this raw materials. Until then a
Survey UZ Leuven
In 2007 UZ Leuven started an orphan diseases task force to survey the use of orphan drugs
in the hospital. Over 100 orphan diseases were reported, 18 orphan drugs and 11 orphan
raw materials are used with a budget of € 7,000,000 in the year 2007. UZ Leuven treats
over 2000 patients with orphan drugs. In 2008 the task force advised and requested the
foundation of the “Leuven coordination center for rare diseases and their treatments”
Pompe disease
In 1932 Johann Pompe first described an autosomal recessive metabolic disorder affecting
the enzyme acid maltase. The disease is also known as glycogen storage disease type II
enzyme deficiency. The infantile or early onset is noticed shortly after birth and most of the
children will die before the age of two of respiratory or cardiac complications.
Therapy exist in administering a replacing enzyme that can break down glycogen. In 2001
Genzyme coordinated a clinical trial with alpha-glucosidase. Only one patient was included
in Belgium.
Thanks to the therapy the patient could survive but is depended on a wheelchair and special
care. The hospital pharmacist had a big role in finetuning the method of preparation,
administration and was facilitator in studying extended stability of the solution. After 5-6
Fabry disease
A similar autosomal recessive metabolic disorder concerns the deficiency of the enzyme
causes Fabry disease. For the treatment of this disorder two subtypes of the enzyme
For the treatment of pulmonary arterial disease five orphan drugs are authorized. This
lungs caused by vasoconstriction and is leading to hearth failure and long fibrosis.
Conventional treatment exists of lifestyle changes, digoxin, diuretics, oral anticoagulants and
(Flolan). With this therapy patients could survive until a donor for lung transplantation was
venous catheter. Due to its unstability (t½ = 5 minutes) the solution has to be kept on ice
carry the pump reservoirs in cooled conditions. Right now other prostaglandins like
treprostinil (Remodulin) and iloprost (Ilomedine) with other farmacokinetic parameters are
available and give patients more comfort and flexibility. In Asia en the USA oral
prostaglandins are available. Also endothelial receptor antagonists are influencing the
symptoms and can be used in therapy. In Belgium bosentan (Tracleer) and sitaxentan
(Thelin) are available for oral administration. In the group of phospdiesterase inhibitors
sildenafil (Viagra and Revatio) are available. Supplements of L-arginin are available as
Parkinson disease
In some severe degrees of Parkinson disease a patient can have on-off fluctuations. This can
be explained by 38 % variability in plasma levels caused by the small half life of levodopa and
the erratically absorption in the stomach of severe Parkinson patients resulting in peaks and
throughs in the plasma levels. When levodopa and carbidopa are given in the jejunum this
variability drops back to 17 % while the patients on-off fluctuations disappears. The
intestinal gel is given by a CADD-pump through a nasal-jejunal probe (or a button). The
product is marketed as a ready to use solution with a stability of only 15 weeks in the
refridgerator and 16 hours at body temperature. The therapy has a cost of € 45,000 / year
/ patient.
In 1912 Samuel Wilson first described an autosomal recessive genetic disorder which is
basically a accumulation of copper in the tissues of the body. The symptoms vary from liver
disease to neurological and psychiatric problems but one of the most typical is the presence
of a Keyser-Fleischer ring in the eyes. Besides copper also calcium is accumulated in the
of Wilson disease is very simple and exists of a low copper diet combined with copper
chelation by penicillamin. But there’s also a natural way of binding the metal. Zinc acetate
activates methallothionein, a protein in the gut, that binds copper so it cannot be adsorbed
and transported to the liver. But in the end the patient will probably need a liver
transplant.
Conclusions
The definitions of orphan diseases and orphan drugs depend on the country and the need to
grant the status depends on the population. So a certain disease can be common in the
West while it is rare in the East. Once a product is recognized as an orphan drug the
manufacturer gets financial incentives to market the drug. In most cases this is related to a
high vending price resulting in very expensive therapies in which pharmacists play an
important role in advising, preparing, dispensing and managing financials (eg reimbursement).
In Europe EMEA is supporting and facilitating. The transparency of their assessment can be
seen in the online publication of the European Public Assesment Report (EPAR) in which
In spite of the given incentives not al needed molecules are available as orphan drug. This
leads to problems in tertiary care hospitals where these drugs are needed on a nearly daily
basis to treat the rare patients. The Royal Decree of 1997 will forbid the use of non
use these orphan raw materials wil be defined leading us out of the twilight zone.
Nevertheless ethical and macro farmaco-economical discussions in this domain will be of all
times.
Reflection
Orphan drugs is just a special status for medication that is needed to treat uncommon
diseases. But what is the difference with compassionate use, medical need, clinical trials,
conventions and off label use … aren’t they all just names to define a way in which people
can be helped when the commonly available medication fails to do the job ?