Mixed assessment in Europe - SURVEY Drugs for rare diseases: Prescrire IN ENGLISH
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Translated from Rev Prescrire November 2006; 26 (277): 780-787
Drugs for rare diseases:
SURVEY
mixed assessment in Europe
● Worldwide, there are an estimated ● In 2000 the European Union adopt- tance as well as a 10-year marketing
6000 to 7000 rare diseases. Patients face ed a Regulation, based on experience in monopoly.
special difficulties in obtaining an accu- the United States, aimed at promoting
rate diagnosis, adequate information the development of drugs for patients ● Between April 2000 and April 2005,
about the disease, and access to quali- suffering from rare diseases, i.e. ‘orphan 268 medicinal products received Euro-
fied specialists. drugs’. pean orphan drug status and 22 were
granted European marketing authori-
● Drug companies do not sponta- ● In Europe, orphan drug status can be sation.
neously conduct research on drugs for granted when the prevalence of the dis-
rare diseases, mainly because of the lim- ease does not exceed 5 cases per 10 000 ● Access to these drugs varies greatly
ited market for each indication. Only a inhabitants (or when it is more frequent from one European Union Member
few dozen of these drugs were available but profitability is likely to be inadequate). State to another, mainly because of the
in France before 2000. high annual treatment costs (up to
● Companies that market an orphan 300 000 euros per patient). Worldwide
drug receive a variety of financial assis- sales of the orphan drug imatinib reached
36 • P R E S C R I R E I N T E R N A T I O N A L F E B R U A R Y 2007/ V O L U M E 1 6 N ° 8 7
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in 2005. More than 20 years of orphan drug legislation
● Our systematic analyses (see the New in the United States
Products column of our French edition
la revue Prescrire) show that only 5 drugs Since 4 January 1983 (the date the Orphan Drug Act was passed by the US Congress) the
which received European orphan drug American authorities have had at their disposal a system of incentives for the development
status before May 2005 were for diseases and marketing of drugs for patients with rare diseases (1). Various amendments have extend-
for which there had previously been no ed its application to medical devices, biological products and dietary products (2).
treatment. A disease is considered “rare” in the United States if it affects fewer than 200 000 people,
i.e. if it has a prevalence of less than 8 cases per 10 000 inhabitants (a), or, alternatively, if it
● Clinical evaluation of orphan drugs affects more that 200 000 people but the development and distribution costs are not likely
is hindered by the small number of to be recouped through national sales (1).
patients available for clinical trials. Some Official orphan product status is granted by the FDA Office of Orphan Products Devel-
orphan drugs are adequately tested opment (OOPD) (1,2). Application for approval follows at a later date (b). According to the
before being brought to market. Oth- FDA website, as of 31 July 2006, about 1600 pharmaceutical and biological products have
ers are not compared to existing treat- been granted orphan status. In total, 286 drugs designed for the treatment of patients with
ments. In many cases, surrogate crite- rare diseases have received marketing approval (fewer than 10 in the 1970s, 108 between
ria are used instead of clinical endpoints. 1984 and 1994, and more than 160 between 1995 and 2005) (3).
These methodological flaws are in no The American system gives manufacturers of orphan drugs a 7-year market exclusivity
way limited to orphan drugs. (starting on the date of approval), and a tax break that can cover up to 50% of the costs of
clinical trials conducted in the United States for the relevant indication (c)(2). Since 1992, a
● Not all orphan drugs represent ther- new drug similar to a drug already marketed for an orphan indication can also be granted
apeutic advances. Clinical research and orphan drug status if it is shown to be clinically superior (2).
evaluation should continue after mar- ©Prescrire
keting authorisation has been granted.
● More drugs, with better-document- a- In Japan a disease is considered “rare” if its prevalence is no more than 4 per 10 000. In Australia the prevalence
is 1.1 per 10 000 Australian inhabitants (ref 4).
ed efficacy and safety, are now available
b- A drug can be made available before marketing authorisation is granted, through a compassionate use programme
for patients who previously had no effec- (Investigational New Drug Treatment (t-IND)) (ref 2).
tive treatment options. Yet there is too c- The National Institutes of Health (NIH) have a 5-yearly budget of 71 million dollars for clinical trials in rare dis-
much duplication and too little evalua- eases (ref 5).
tion, and too many drugs are extreme-
ly expensive, meaning that patients in 1- U.S. Food and Drug Administration “The Orphan Drug Act (as amended)” Website http://www.fda.gov
many European countries cannot ben- accessed 6 July 2006: 6 pages.
efit. And many rare diseases are still 2- Orphanet “Les médicaments orphelins aux États-Unis d’Amérique” Website http://www.orpha.net
accessed 6 July 2006: 3 pages.
neglected. 3- “Orphan disease research may require new incentives” Scrip 2006; (3152): 19.
4- Orphanet “Comparaison des différentes politiques du médicament orphelin à travers le monde” Web-
Rev Prescrire 2006; 26 (277): 780-787. site http://www.orpha.net accessed 6 July 2006: 1 page.
5- U.S. Department of Health and Human Services - National Institutes of Health “NIH launches clinical
studies nationwide to investigate rare diseases” Website http://www.nih.gov accessed 10 July 2006:
3 pages.
S
ix years after European Union Regu-
lation EC 141/2000 went into effect,
on 22 January 2000, the European
Medicines Agency (EMEA) and the Euro- An estimated 6000 to 7000 rare diseases A questionnaire-based survey of rare dis-
pean Commission examined its impact in have so far been identified worldwide, and eases conducted in 2002, involving
the development and marketing of drugs for most are genetic in origin (6). There are 6000 patients/families residing in 17 EU
patients with rare diseases (‘orphan drugs’), under 500 published cases for about 200 of Member States, showed that 25% of patients
between April 2000 and April 2005 (1-3). these diseases in Europe (7). In France about waited between 5 and 30 years after the onset
We take this opportunity to examine this 50 rare diseases affect several thousand peo- of symptoms before obtaining a correct diag-
policy (4,5), particularly with respect to the ple each (cystic fibrosis and Duchenne’s nosis. 40% of patients initially received an
number of orphan drugs now marketed in myopathy, for example), while another incorrect diagnosis, resulting in unnecessary
Europe, how they were assessed, their risk- 500 affect a few hundred people each surgery in 16% of cases, inappropriate drug
benefit balances, their availability in Euro- (leukodystrophy for example). Other diseases therapy in 33%, and inappropriate psycho-
pean Union Member States, and their cost. affect only a dozen or so people in the entire logical management in 10% (a)(10). In
world; one example is progeria, a form of
premature aging (8).
Rare diseases: difficulties
a- The eight diseases were Crohn’s disease, cystic fibrosis,
for the patients concerned An obstacle course for patients. Peo- Duchenne’s myopathy, Ehlers Danlos syndrome, fragile
ple with rare diseases, and their families, have X syndrome, Marfan’s syndrome, the Prader-Willi syn-
Regulation EC 141/2000 defines rare dis- difficulties obtaining the correct diagnosis, drome, and tuberous sclerosis (ref 10). This survey was
conducted by the European Organization for Rare Diseases
eases as those with a prevalence of no more adequate information concerning their dis- (Eurordis), an umbrella group of associations of patients
than 5 per 10 000. Assuming that the 25 EU ease, and referral to a specialist (6,9). Their with rare diseases. Eurordis was created in 1997 by the
Member States include a total of about medical and social management is sometimes Association Française contre la Myopathie (AFM), the
Ligue française contre le cancer (Fnclcc) and the Fédéra-
450 million inhabitants, this corresponds to inappropriate, with individual families often tion française contre le HIV (Aides), along a similar model
fewer than 225000 patients (about 30000 in having to shoulder a large part of the finan- to the North American National Organization for Rare
France) (1,6). cial burden. Disorders (NORD) (ref 65).
P R E S C R I R E I N T E R N A T I O N A L F E B R U A R Y 2007/ V O L U M E 1 6 N ° 8 7 • 37
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order to obtain the correct diagnosis, 25% Nearly 20 years after the United States’
Orphan: of patients had to go to another region and initiative, and largely based on experience
2% to another country. Many patients/fam- in that country, Regulation EC 141/2000 pro-
an ambiguous term ilies said the diagnosis was provided in a tact- vided a series of incentives for drug compa-
less or uninformative manner (10). nies to develop and market orphan drugs in
Orphan drug. The term ‘orphan drug’ These difficulties lead to waste in terms of the European Union (1). The Committee for
was first used in the United States, before unnecessary delays and inappropriate use Orphan Medicinal Products (COMP), com-
being adopted in European Regulations. This of healthcare resources. There is a move- posed of specialists and representatives of
term is ambiguous, however. ment to create European multidisciplinary patient or family groups, is now responsible
All orphan drugs have at least one indi- reference centres for rare diseases (or groups for examining applications submitted by
cation in a rare disease (imatinib, for exam- of rare diseases), based on existing infra- companies seeking to qualify for the eco-
ple, has several indications in rare diseases), structure in Belgium, Denmark, France, Italy, nomic advantages of orphan drug status.
and some have indications in both rare and the United Kingdom and Sweden (11).
frequent diseases (for example, sildenafil is Orphan drug status. According to the
indicated in both pulmonary hypertension Uneven access to drugs.With the excep- Regulation, orphan drugs are products
and erectile disorders). tion of drugs that have been granted orphan designed for the diagnosis, prevention or treat-
We propose replacing the term ‘orphan status (as defined by Regulation EC 141/2000) ment of a rare disease, and defined by 2 cri-
drug’ with ‘drug for a rare disease’, which and off-licence uses of drugs developed for teria: either epidemiological criteria (a dis-
is more accurate. other diseases, the obstacles faced by patients ease affecting “not more than 5 in 10 thousand
seeking drug therapy for rare diseases vary persons in the European Community when the
Rare disease. The term ‘rare disease’ among EU Member States. Options that application is made”; or economic criteria (a
refers to a disease that only affects a small were available before the enactment of the disease that “without incentives it is unlikely
minority of the general population. The term EU Regulation included compassionate-use that the marketing of the medicinal product in
‘rare disease’ implies that the disease in programmes, temporary approval (on a the Community would generate sufficient return
question can be diagnosed, and that its inci- cohort or named-patient basis), drug com- to justify the necessary investment” (1).
dence and prevalence in a given population pounding by a hospital pharmacy, partici- To obtain orphan drug status, a company
can be estimated with a reasonable degree pation in clinical trials, and European or has to submit an application to EMEA for
of accuracy. national marketing authorisation (12,13). orphan drug designation of a given sub-
The threshold incidence or prevalence stance in a given indication, which is placed
below which a disease can be considered Situation prior to the EU Regulation. on a Community register of orphan drugs
rare is arbitrary. It is different in the Unit- In France a dozen drugs for rare diseases had (b)(1). Designation as an orphan drug does
ed States and the European Union, for exam- been approved before Regulation EC not mean that the product will automati-
ple. 141/2000 came into force. They included cally receive marketing approval.
A rare disease is not necessarily a neglect- alglucerase (subsequently replaced by The manufacturer must provide: infor-
ed disease. For example, several drugs are imiglucerase) and a C1 esterase inhibitor. mation on the prevalence of the disease and
marketed for pulmonary hypertension, which About 60 products were available through its severity; the lack of satisfactory means to
is considered a rare disease. temporary licences in 2005, or through clin- diagnose, prevent or treat the condition; a
ical trial participation, or in the form of hos- better risk-benefit balance than existing
Neglected diseases. Neglected dis- pital pharmacy compounding (for example, treatments; and the likely return on invest-
eases are diseases for which there are few D-mannose for a form of abnormal protein ment (including the costs of development,
or no treatment options, and for which no glycosylation) (13,14). production and marketing, and sales fig-
meaningful research is underway. Six ‘orphan-like’ drugs received European ures expected during the first ten years)
A neglected disease is not necessarily a marketing authorisation between 1996 and (1,17).
rare disease. Many parasitic infections affect 2000, before Regulation EC 141/2000 was At this stage, there may be no available
large numbers of people in poor countries enacted: cysteamine, imiglucerase, tasoner- clinical data , only the results of animal exper-
but are neglected because of the lack of mine, sodium phenylbutyrate, clotting fac- iments or in vitro studies showing the “med-
research into treatments. This is the case tor IX, and samarium lexidronam (15). These ical plausibility” of using the substance in
for sleeping sickness, Kala-azar, Chagas dis- drugs are considered “orphan-like” because question in its intended indication (2,18).
ease, etc. the companies concerned benefited from the
©Prescrire advantages provided by Regulation EC European marketing authorisation.
141/2000. After receiving orphan drug status for a prod-
uct, the company submits a marketing appli-
cation to EMEA. The centralised procedure
A European incentive policy has been required since 20 November 2005
(2).
Companies are reluctant to develop and The application must include pharma-
market drugs for patients with rare diseases, ceutical and chemical sections guaranteeing
mainly because these products cannot be the same level of pharmaceutical quality as
patented (well-known chemicals or natur- for other drugs, and also toxicological, phar-
al extracts), and/or because the limited num- macological and clinical sections. These last
ber of patients would not make production three parts are often less substantial for
profitable (16). orphan drugs than for other drugs: large tri-
Under pressure from patient groups, the als are often impossible to conduct, given
United States was the first country to create the obvious problem of patient recruitment.
incentives for manufacturers to develop and
market drugs for rare diseases, in 1983 (see Economic advantages. Orphan drug
inset page 37), followed by Japan in 1993, status provides a number of advantages for
and by Australia and Singapore in 1998 (4). the companies that market these products.
38 • P R E S C R I R E I N T E R N A T I O N A L F E B R U A R Y 2007/ V O L U M E 1 6 N ° 8 7
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Copyright(c)Prescrire. For personal use only.These include: free technical assistance from available in 15 EU Member States, while the
EMEA in preparing the application; a 50% second (study period not specified) con- Imatinib: an example
reduction in EMEA fees (paid for out of a cerned 10 orphan drugs in 25 EU Member
Community fund) (c); and a 10-year pan- States (12,20). According to this second, not to be repeated
European market exclusivity starting on the more extensive study, about half the
date that marketing authorisation is grant- 25 orphan drugs were effectively marketed Although economic data are incomplete,
ed (1,3). in 15 of the 25 EU Member States (12). orphan drugs seem to account for between
Individual Member States can also take Patients living in countries where these drugs 0.7% and 1% of all drug costs in rich coun-
additional measures (especially tax incen- are reimbursed (Germany, Spain, France, tries, but this could reach 6% to 9% by 2010
tives) to support manufacturers based in The Netherlands, and Sweden) have better (1). What used to be considered a “niche”
their countries (d)(1,3,4). access (12). The annual average cost of treat- has become a full-fledged market.
These incentives come with several con- ing a patient with an orphan drug is high, Take imatinib for example. Worldwide
ditions, however. In particular, the market ranging from 2000 euros to 300 000 euros sales reached about 2.17 thousand million
exclusivity can be reduced to 6 years if, after (12). Some orphan drugs, such as imatinib dollars in 2005 (1.63 in 2004; 1.13 in 2003;
5 years, it emerges that the orphan-drug cri- (see inset opposite), have even become block- 0.62 in 2002; 0.17 in 2001), representing
teria are no longer met: for example, if the busters with global sales reaching several about 10% of total income for the manu-
epidemiological situation changes and the thousand million dollars. The cost of using facturer, Novartis (2). In France, imitanib
disease is no longer rare or if profits prove a given orphan drug differs by up to 70% cost the health insurance system more than
to be adequate (1). between the 25 EU Member States (12). Dif- 100 million euros in 2005 (for about 3000
In addition, a “similar” drug can be ferences in taxes, distribution circuits and patients), ranking tenth in treatment expen-
approved for the same indication as an dispensing practices are factors that influ- diture (3).
orphan drug, despite the initial product’s mar- ence the price. European marketing authorisation and
ket exclusivity, if one of the following con- orphan drug status were first granted for
ditions is met: the holder of the marketing imatinib in 2001 for the treatment of a form
authorisation for the initial orphan drug Unequal assessment of myeloid leukaemia. There were few
does not produce it in adequate amounts, of orphan drugs patients with this condition, which partly
or the second drug has a better risk-benefit justified the high price.
balance than the first (1,17,19). The Prescrire editorial team had examined The indications were then extended to
the evidence on 22 drugs granted European include other forms of myeloid leukaemia
orphan drug status up to May 2005. The and then gastrointestinal stromal tumours.
22 European marketing resulting review articles have either been Five new indications are currently being
authorisations in 5 years published in the Journal or are in press (21- examined by the European Medicines Agency
61). The analysis also includes imiglucerase, (Darier-Ferrand dermatofibrosarcoma,
Between April 2000 and April 2005, 268 which had already been approved before the acute lymphoblastic leukaemia, myelodys-
medicinal products (out of 458 applications) period covered by the European Medicines plasia and related disorders, mastocytosis,
were designated as orphan drugs for the treat- Agency report (April 2000-May 2005), but chronic eosinophilic leukaemia, and the
ment of about 200 diseases: cancer (36% of which, during this same period, was grant- hypereosinophilia syndrome) (4).
cases), metabolic disorders (11%), immuno- ed a licence extension to cover type3 Gauch- Thus, 5 years after imatinib was first mar-
logical disorders (11%), cardiorespiratory er’s disease (30). These 23 drugs are approved keted, the notion of “rarity” needs to be
conditions (10%), musculoskeletal and ner- for 21 different indications (see table page40). revisited. It is unacceptable that the price
vous system disorders (8%), infections (4%), remains at the current high level.
and miscellaneous conditions (20%) (2,3). A rare disease is not always an orphan ©Prescrire
Eleven percent of these orphan drugs were disease. Although most rare diseases are
developed only for children, 46% only for genetic in origin, only 8 of these 21 indica- 1- European Social Health Insurance Forum
adults, and 43% for both populations (2,3). tions involve hereditary diseases, and only “Consultation on a general report on the expe-
When the applications for orphan drug 4 of the 8 corresponding drugs represent rience acquired as a result of the application of
Regulation (EC) n°141/2000 on orphan medic-
status were submitted to EMEA, the preva- replacement therapy (Fabry’s disease, type inal products and account of the public health
lence of the diseases was less than 1 in 10000 I mucopolysaccharidosis, and type 1 and benefits obtained. Comments of the Medicine Eval-
in 43% of cases, between 1 and 3 per 10 000 type 3 Gaucher’s disease). uation Committee (MEDEV)” March 2006:
4 pages.
in 47% of cases, and between 3 and 5 per 2- Novartis “Full year results” Website
10 000 in 10% of cases (2,3). http://www.novartis.com accessed 10 July 2006:
By April 2005, 19% of the manufactur- 6 pages.
3-French Assurance maladie “Médicaments rem-
ers that had obtained orphan drug status had b- This registry is available on the website of the European boursables: analyse des principales évolutions de
submitted marketing applications: 44 through Commission’s Enterprise Directorate at http://ec.europa.eu/ l’année 2005” Website http://www.ameli.fr
enterprise/pharmaceuticals/index_en.htm accessed 10 July 2006: 9 pages.
the centralised procedure and 5 through a
c- The total tax breaks covered by the Community fund 4- European Commission “Register of designat-
national procedure (3). Twenty products grew from 28 000 euros in 2000 to 3 988 700 euros in 2004 ed orphan medicinal products”. Website http://ec.
received European marketing authorisation (ref 2). In 2005 the Community fund amounted to 3700000 europa.eu/enterprise/pharmaceuticals/index_en.
through the centralised procedure, and two euros, but estimated needs reached 6 000 000 euros because htm accessed 14 September 2006: 2 pages.
of the increase in requests to COMP for technical assistance
by mutual recognition of national approval and post-marketing follow-up (ref 2).
(levodopa-carbidopa duodenal gel, and oral d- In France, for example, drug companies are exempted
miltefosine) (e). from taxes and health insurance contributions; an agree-
ment between manufacturers and the State was settled
by the health products economic committee; some orphan
Major differences in access from one drugs are registered on the list of costly and innovative
country to another.Access to orphan drugs medicinal products (refs 8,66). See reference 67 for infor-
varies greatly between EU Member States, mation on measures taken by other European Union
Member States.
and has been the subject of two studies. The e- In late 2005, 342 products had been designated as
first, conducted between October 2002 and orphan drugs and 24 had received marketing authorisa-
January 2003, focused on five orphan drugs tion (ref 67).
P R E S C R I R E I N T E R N A T I O N A L F E B R U A R Y 2007/ V O L U M E 1 6 N ° 8 7 • 39
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Drugs granted EU marketing authorisation and orphan drug status between April 2000 and April 2005
INN Indications Epidemiology Comparative trials Non comparative trials Prescrire score ASMR Ref.
(a) (b)
Number Patients Endpoints Patients Endpoints
(total)
agalsidase alfa Fabry’s disease (G) P = 0.085 2 26, 15 clinical — — Judgement reserved II (7,21,22,46)
to 0.175
agalsidase beta Fabry’s disease (G) P = 0.085 1 58 surrogate — — Judgement reserved II (7,21,22,46)
to 0.175
anagrelide Essential P = 2.75 1 809 clinical 254,242,34 surrogate Judgement reserved IV (40)
thrombocytemia
arsenic trioxide Acute promyelocytic P = 0.8 0 — — 52 clinical Possibly helpful Not scored (7,23)
leukaemia
bosentan Pulmonary P = 0.15 3 32, 213, 33 clinical Offers an advantage I (7,24)
hypertension — —
busulfan Stem cell grafting NA 3 42, 62, 24 clinical — — (c) — (42)
carglumic acid N-acetyl-glutamate - P = 37 cases 0 — — 16 clinical A real advance I (31)
synthetase deficiency managed
(G) worldwide
celecoxib Familial P=1 1 77 surrogate — — Not acceptable Not available (7,34,55)
adenomatous on 14 Sept. 06
polyposis (G)
cladribine Hairy cell leukaemia I = 100 cases 0 — — 63 surrogate Possibly helpful IV (36,57)
SC in France
ibuprofen Patent ductus P=2 1 (b) 33 (d) surrogate — — Offers an advantage I (7,38,58)
10 mg injectable arteriosus
iloprost Pulmonary P = 0.15 1 203 clinical — — Nothing new II (7,33)
for inhalation hypertension
imatinib Chronic myeloid P = 0.6 0 1 027 surrogate Possibly helpful I (7,25)
leukaemia — —
(last resort)
imatinib Chronic myeloid P = 0.6 1 1 106 clinical — — Interesting I (7,26)
leukaemia (first-line)
imatinib Stromal GI I = 0.1-0.2 3 147, 746, 753 clinical — — Offers an advantage I (27,48)
tract tumours
imiglucerase Gaucher’s disease 5 cases managed 0 — — 60 clinical Possibly helpful I (30,52)
type 3 (G) in France
laronidase Mucopolysaccharidosis P = 0.1 1 45 clinical 10 surrogate Offers an advantage II (7,32)
type 1 (G)
levodopa + Advanced Parkinson’s NA 1 24 clinical Possibly helpful IV (45)
carbidopa disease — —
duodenal gel
miglustat Gaucher’s disease P = 0.5 2 18, 36 surrogate 28 surrogate Possibly helpful Not scored (29,52)
type 1 (G) (53 cases
managed in France)
oral miltefosine Visceral — — — — — — (c) — (44)
leishmaniasis
mitotane Adrenal cancer I = 0.005 0 — — 312 clinical Possibly helpful II (37)
nitisinone Hereditary P = 0.005 0 — — 207 clinical Bravo Not available (7,43)
tyrosinaemia type 1 on 14 Sept 06
pegvisomant Acromegaly P = 0.5 1 112 clinical 7 surrogate Possibly helpful III (7,28)
porfimer Barrett’s high-grade P = 2.2 to 4.6 1 208 clinical — — Judgement reserved II (35,56)
oesophageal
dysplasia
ziconotide Refractory pain NA 3 220, 112, 257 clinical — — (c) Not available (41)
on 14 Sept. 06
zinc acetate Wilson’s disease (G) P = 0.58 1 67 clinical 170 clinical Offers an advantage IV (7,39)
a- The incidence rates (I) and prevalence rates (P) are given per 10 000 inhabitants, unless d- Other trials are available, but with ibuprofen formulations different from the marketed product.
otherwise stated.
b- ASMR: Assessment by the French Transparency Committee (see ref. 63). G: Hereditary disease
c- On 5 October 2006, we had not published our analysis of the clinical data. NA: Not available – we found no reliable estimate of the prevalence or incidence.
40 • P R E S C R I R E I N T E R N A T I O N A L F E B R U A R Y 2007/ V O L U M E 1 6 N ° 8 7
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Copyright(c)Prescrire. For personal use only. Only 5 indications were not previously was not compared with interferon alfa in Questionable therapeutic advance.
treated by a drug with at least partial effica- chronic myeloid leukaemia, even though As our regular readers know, we use an at-
cy (Fabry’s disease, gastrointestinal stromal more than 1000 patients participated in tri- a-glance scoring system (see page 14) to esti-
tumours, type 3 Gaucher’s disease, type I als of second-line treatments for this disease; mate the therapeutic advance represented
mucopolysaccharidosis, and type 1 tyrosine- pegvisomant was compared with placebo in by new drugs, including orphan drugs. The
mia) (21,27,30,32,43). acromegaly, when a trial versus lanreotide French Transparency Committee rates drugs
More than one drug was approved for or octreotide would have been more appro- on the basis of what it calls the ‘improve-
2 separate indications: Fabry’s disease (21,22), priate; ibuprofen for injection was compared ment in medical service rendered’. The two
and pulmonary hypertension (f)(24,33). with placebo in patent ductus arteriosus, scores often diverge (63).
despite the existence of a standard treatment, These divergences are particularly note-
Some drugs were properly assessed. indometacin (26,28,38). worthy when it comes to orphan drugs (see
Clinical evaluation of drugs for rare diseases Three authors with no conflicts of inter- table page 40), mainly because the Trans-
mainly faces two specific obstacles. est, two of whom had served with the EMEA, parency Committee gives a score of I or II
The limited number of patients can make conducted a review of 18 orphan drugs (62). (i.e. major or significant advance) despite
it difficult to conduct dose-finding studies and Their conclusions were similar to ours; they the lack of comparative trials, even when
comparative trials. On the other hand, most also criticised the lack of proper trials (dose- such trials were feasible: this was the case
patients with a given rare disease are man- finding studies alone in 6 indications), the for second-line imatinib in chronic myeloid
aged by a small number of specialised teams, lack of comparative trials versus existing leukaemia, iloprost in pulmonary hyper-
and it is often relatively easy to identify them. standard treatments, and the excessive use tension, mitotane in adrenal cancer, and
Secondly, these are chronic diseases, and it is of surrogate endpoints. In addition, they ibuprofen in patent ductus arteriosus
not always easy to find clinical endpoints or examined animal studies and found that (g)(25,26,33,37,38).
satisfactory surrogate endpoints for relative- genotoxicity studies were lacking for 5 drugs,
ly short-term clinical trials. Dose-finding stud- carcinogenicity studies for 6 drugs, and repro-
ies are available for only 7 of the 21 indica- ductive toxicology studies for 2 drugs. Over- Room for improvement
tions (21,27-29), but the evaluation of many all, they found the evaluations to be of rather
drugs marketed for common conditions suf- poor quality. During a 5-year period, European mar-
fers from the same shortcomings. keting authorisation was granted for 22
Most orphan drugs were tested in ran- Need for transparency. All drug assess- ‘orphan drugs’ for patients with rare diseases.
domised controlled trials before licensing. In ment data should be made public, and this Although insufficient, this is an encour-
other cases, comparative trials could not be is especially important for rare diseases for aging start. Indeed, a large number of drugs
conducted because of the rarity of the dis- which there are fewer data. were already available for rare diseases before
ease such as type 3 Gaucher’s disease and Take agalsidase alfa and agalsidase beta the Regulation came into effect, usually
N-acetyl glutamate synthetase deficiency for example. In the absence of anything bet- approved through national procedures.
(30,31). The Prescrire editorial team consid- ter, our initial review of the evidence was Moreover, European orphan drug status is
ered that a simple historical comparison was essentially based on the EMEA assessment not a panacea, especially in terms of access
acceptable in one setting, in which nitisi- report (21). Some of the data contained in and reimbursement, which vary widely from
none was compared with dietary measures this report were incorrect, however, lead- one EU Member State to another. Rapid and
and proved to be largely beneficial in terms ing us to initially conclude that agalsidase accurate diagnosis of rare diseases is also cru-
of survival (43). In 3 cases the absence of alfa ‘offered an advantage’ and that agalsi- cial for appropriate patient management,
comparative trials was more questionable: dase beta represented ‘nothing new’ (21). and this has led some Member States (includ-
second-line imatinib for chronic myeloid The FDA released their assessment reports ing France) to create specific reference cen-
leukaemia (1027 patients enrolled in non on these two drugs after our article had been tres.
comparative trials), mitotane for adrenal published. Although they were based on the Five years after the first marketing autho-
cancer (312 patients enrolled in non com- same two trials as those examined by the risation was granted for an ‘orphan drug’,
parative trials), and busulfan conditioning European agency, the FDA analysis was the initial evaluation data vary in quality,
prior to stem cell grafting (25,37,42). more precise and provided new information but no more so than for other drugs. Ques-
Some drugs were tested in trials with only that led us to revise our initial ratings for the tions remain concerning the quality of post-
surrogate endpoints even though the use of two drugs. They became ‘judgement reserved’ marketing surveillance, especially the nec-
clinical endpoints was feasible: in Fabry’s dis- for both products (22). essary periodic reassessments of risk-bene-
ease agalsidase alfa was assessed on the basis fit balances and the transparency of the
of clinical endpoints, and agalsidase beta Inadequate post-marketing surveil- results.
only on surrogate endpoints; and the assess- lance.The initial evaluation of drugs for rare Regulation EC 141/2000 is intended to
ment of second-line imatinib for myeloid diseases often leaves many unanswered encourage the development and marketing
leukaemia was not based on clinical criteria questions, which is to be expected consid- of drugs designed for patients with rare dis-
such as mortality (21,22,25). ering the small number of patients enrolled eases, in exchange for tax incentives for the
in clinical trials and the relatively short-term manufacturers concerned. Some drug com-
Controversial comparisons. Some dis- follow-up. This makes post-marketing sur- panies have been granted very high prices
eases are simply too rare to conduct com- veillance studies all the more crucial. for their products, to the point that some
parative studies; for example, cladribine and Patients are usually identified by drug
interferon alfa cannot be compared in hairy- companies and/or managed by a few spe-
cell leukaemia, a disease only affecting cialised teams, making it relatively simple f- Sildenafil is also indicated for pulmonary hypertension
100 patients in France (23,36). The lack of to compile patient registries. But this is not (ref 68). It is not included in this analysis, because it was
approved after the end of the study period (April 2000 to
randomisation was also justified in the com- enough. These registries must contain per- April 2005).
parative study of zinc acetate and penicil- tinent information, be appropriately g- In the case of ibuprofen, our conclusion that it ‘offers an
lamine in Wilson’s disease, as the two drugs analysed at regular intervals, and be made advantage’ was mainly based on the fact that this is the
only drug approved for this use, which guarantees its phar-
are used in different contexts (39). available to patients and caregivers. There maceutical quality and facilitates access to treatment. In the
In other cases the lack of comparative is currently no such system in the Euro- absence of direct comparisons, it is not certain that its risk-
studies is more difficult to justify: imatinib pean Union. benefit balance is better than that of indometacin.
P R E S C R I R E I N T E R N A T I O N A L F E B R U A R Y 2007/ V O L U M E 1 6 N ° 8 7 • 41
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42 • P R E S C R I R E I N T E R N A T I O N A L F E B R U A R Y 2007/ V O L U M E 1 6 N ° 8 7
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