Mixed assessment in Europe - SURVEY Drugs for rare diseases: Prescrire IN ENGLISH

Mixed assessment in Europe - SURVEY Drugs for rare diseases: Prescrire IN ENGLISH
Outlook                                                         POSITION

Translated from Rev Prescrire November 2006; 26 (277): 780-787

    Drugs for rare diseases:

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

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more than two thousand million dollars
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.

      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).

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Outlook                                                         SURVEY

                                                                     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
                                                                     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.

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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).

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Outlook                                                          SURVEY

                   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
 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)

 arsenic trioxide Acute promyelocytic       P = 0.8              0          —                —                    52              clinical         Possibly helpful         Not scored       (7,23)

 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)

 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)

 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.

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 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.

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Outlook                                                         SURVEY

 orphan drugs have become blockbusters                           traitements de maladies rares et graves” June 2005:          43- Prescrire Rédaction “nitisinone (Orfadin°).
in only 5 years. Regulation EC 141/2000                           12 pages.                                                    Tyrosinémie de type 1 : un médicament efficace” Rev
                                                                  14- Agence française de sécurité sanitaire des pro-          Prescrire 2006; 26 (276): 654 (full version available
includes a provision that market exclusivi-                       duits de santé “Rapport annuel 2005”: 142 pages.             on www.prescrire.org : 3 pages) (to be translated in
ty can be reduced from 10 years to 6 years.                       15- European Medicines Agency “Status report on              Prescrire International - April issue).
But will this provision be applied, and how                       the implementation of the European parliament leg-           44- German regulatory agengy “Résumé des carac-
                                                                  islation on orphan medicinal products” 30 March              téristiques du produit-Impavido° 10 mg gélules-
will adequate profitability after 5 years be                      2001: 3 pages.                                               Impavido° 50 mg gélules” January 2005: 6 pages.
determined? Should only the ‘orphan’ indi-                        16- Prescrire Editorial Board “Le point de vue d’un          45- Prescrire Rédaction “lévodopa + carbidopa gel
cation be taken into account, or all possible                     industriel spécialisé” Rev Prescrire 1998; 18(190): 869-     duodénal-Duodopa°. Un autre recours médica-
indications of a given drug, for example ima-                     870.                                                         menteux” Rev Prescrire 2006; 26 (277): 735.
                                                                  17- “Commission Regulation (EC) No 847/2000 of               46- Prescrire Rédaction “La maladie de Fabry. Une
tinib, sildenafil (also used in erectile disor-                   27 April 2000 laying down the provisions for imple-          maladie enzymatique très rare” Rev Prescrire 2002; 22
ders) or celecoxib? Also, in which geographic                     mentation of the criteria for designation of a medic-        (234): 817 (full version available on www.
region should profitability be evaluated: in                      inal product as an orphan medicinal product and def-         prescrire.org: 6 pages).
                                                                  initions of the concepts ‘similar medicinal product’         47- Prescrire Rédaction “Traitement de la leucémie
a Member State, in the entire European                            and ‘clinical superiority’” Official Journal of the Euro-    aiguë promyélocytaire” Rev Prescrire 2004; 24 (248):
Community, or worldwide? How should                               pean Communities 28 April 2000: L103/5-L103/8.               218.
sales volume be measured? And, will these                         18- Héron E “Les médicaments orphelins en Europe”            48- Prescrire Rédaction “L’hypertension artérielle
                                                                  Méd Sci 2005; 21 (n° spécial): 66-68.                        pulmonaire. Grave quand elle est symptomatique”
economic data be made public?                                     19- European Commission “Draft for public consul-            Rev Prescrire 2004; 24 (256): 843-846.
   Public research investment in the EU has                       tation. European Commission guideline on aspects             49- Prescrire Rédaction “La leucémie myéloïde
lagged far behind that of the United States                       of the application of article 8 of regulation (EC)           chronique. Des traitements souvent peu satisfaisants”
                                                                  n°141/2000: Assessment of similarity and/or clinical         Rev Prescrire 2002; 22 (234): 840-842.
(64). The main research incentive for drug                        superiority of orphan medicinal products when assess-        50- Prescrire Rédaction “Les tumeurs stromales du
companies is profit. In many cases, treat-                        ing marketing authorisation applications and varia-          tube digestif” Rev Prescrire 2003; 23 (239): 379-380.
ments with more or less efficacy already exist-                   tions” 2004 Website http://europa.eu.int/comm/               51-Prescrire Editorial Staff “Acromegaly and its treat-
                                                                  enterprise/pharmaceuticals/index_en.htm: 20 pages.           ment” Prescrire Int 2005; 14 (75): 12-13.
ed before orphan drug status was granted                          20-European organisation for rare diseases “Eurordis         52- Prescrire Editorial Staff “Gaucher’s disease” Pre-
for a new product. As a result, even research                     survey of orphan drugs availability and pricing in EU        scrire Int 1996; 5 (23): 72.
on orphan drugs fails to be adequately tar-                       member states” 2003: 10 pages.                               53- Prescrire Rédaction “Les déficits enzymatiques
geted to unmet patient health needs. Reg-                         21- Prescrire Editorial Board “agalsidase alfa-Repla-        de la synthèse de l’urée, maladies orphelines” Rev
                                                                  gal°, bêta - Fabrazyme°. Premier traitement substi-          Prescrire 2001; 21 (214): 109-110.
ulations governing drugs for rare diseases                        tutif pour la maladie de Fabry” Rev Prescrire 2002; 22       54- Prescrire Rédaction “La mucopolysaccharidose
should be refocused on diseases that are                          (234): 817 (full version available on www.                   de type I” Rev Prescrire 2004; 24 (253): 575-5 - 575-
both rare and neglected. There is still no treat-                 prescrire.org: 4 pages).                                     6.
                                                                  22- Prescrire Editorial Staff “Agalsidase” Prescrire Int     55- Prescrire Rédaction “Polypose adénomateuse
ment for several thousand rare diseases.                          2003; 12 (67): 168-171.                                      familiale. Surveillance coloscopique et colectomie
                                              ©Prescrire          23- Prescrire Editorial Staff “Arsenic trioxyde” Pre-        systématique” Rev Prescrire 2005; 25 (265): 691-695.
                                                                  scrire Int 2004; 13 (72): 135-137.                           56- Prescrire Rédaction “L’endobrachyœsophage,
                                                                  24- Prescrire Editorial Staff “Bosentan” Prescrire Int       alias œsophage de Barrett” Rev Prescrire2005;25(267):
                                                                  2005; 14 (77): 94-98.                                        849-851.
                                                                  25-Prescrire Editorial Staff “Imatinib in chronic myeloid    57- Prescrire Rédaction “La leucémie à tricholeuco-
Selected references from Prescrire’s literature                   leukaemia” Prescrire Int 2003; 12 (49): 49-52.               cytes” Rev Prescrire 2006; 26 (270): 209-1-209-2.
search.                                                           26- Prescrire Editorial Staff “Imatinib in first-line        58- Prescrire Rédaction “Canal artériel persistant du
1- “Regulation (EC) no 141/2000 of the European                   treatment for chronic myeloid leukaemia” Prescrire           prématuré” Rev Prescrire 2006; 26 (270): 203-205.
Parliament and of the Council of 16 December 1999                 Int 2003; 12 (68): 216-218.                                  59- Prescrire Rédaction “La maladie de Wilson. Limi-
on orphan medicinal products” Official Journal of                 27-Prescrire Editorial Staff “Imatinib in gastrointestinal   ter la surcharge en cuivre” Rev Prescrire2001; 21(216):
the European Communities 22 January 2000: L18/1-                  stromal tumours” Prescrire Int 2003; 12 (67): 163-           258-259.
L18/5.                                                            164.                                                         60- Prescrire Rédaction “La thrombocytémie essen-
2- European Medicines Agency “COMP report to the                  28- Prescrire Editorial Staff “Pegvisomant” Prescrire        tielle. Cytotoxiques et antiagrégants trop peu évalu-
Commission in relation to article 10 of Regulation                Int 2005; 14 (75): 10-13.                                    és” Rev Prescrire 2006; 26 (269): 123-125.
141/2000 on orphan medicinal products” 25 July                    29- Prescrire Editorial Staff “Miglustat” Prescrire Int      61- Prescrire Rédaction “La tyrosinémie héréditaire
2005: 91 pages.                                                   2005; 14 (79): 168-170.                                      de type 1” Rev Prescrire 2006; 26 (276): 697-1-1.
3-Commission of the European communities “Com-                    30- Prescrire Editorial Staff “Imiglucérase” Prescrire       62- Joppi R et al. “Orphan drug development is pro-
mission staff working document on the experience                  Int 2005; 14 (80): 221.                                      gressing too slowly” Br J Clin Pharmacol 2006; 61 (3):
acquired as a result of the application of Regulation             31- Prescrire Editorial Staff “Carglumic acid” Prescrire     355-360.
(EC) n°141/2000 on orphan medicinal products and                  Int 2004; 13 (69): 3-4.                                      63- Prescrire Editorial Staff “Comparative advantage
account of the public health benefits obtained”                   32- Prescrire Editorial Staff “Laronidase” Prescrire Int     of new drugs: French authorities are not sufficient-
20 June 2006. Website http://europa.eu.int/comm/                  2004; 13 (74): 217.                                          ly demanding” Prescrire Int 2005; 14 (76): 75-79.
enterprise/pharmaceuticals/index_en.htm: 32 pages.                33- Prescrire Editorial Staff “Iloprost in pulmonary         64- Philipson L “Medical research activities, funding,
4- Prescrire Rédaction “Médicaments orphelins.                    hypertension” Prescrire Int 2006; 15 (83): 101.              and creativity in Europe. Comparison with research
L’Europe comble son retard” Rev Prescrire 1998; 18                34- Prescrire Editorial Staff “Celecoxib in prevention       in the United States” JAMA 2005: 294 (11): 1394-
(190): 868-869.                                                   of colorectal cancer” Prescrire Int 2006; 15 (81): 13-       1398.
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règlement européen enfin adopté” Rev Prescrire 2000;              35- Prescrire Editorial Staff “Porfimer in endo-             Introduction” Site Internet http://www.eurordis.org
20 (206): 382-383.                                                brachyesophagus” Prescrire Int 2006; 15 (82): 58-59.         accessed 10 July 2006: 2 pages.
6- Orphanet “Les maladies rares” Website                          36- Prescrire Rédaction “cladribine par voie sous-           66- “Accord cadre entre le Comité économique des
http://www.orpha.net accessed 7 July 2006: 4 pages.               cutanée (Litak°)” Rev Prescrire 2006; 26 (270): 180.         produits de santé et les entreprises du médicament
7- Orphanet “Prévalence des maladies rares: une                   37- Prescrire Rédaction “mitotane-Mitotane PCH°.             pour la période 2003-2006” 2003: 12 pages.
enquête bibliographique” June 2006: 14 pages.                     Un traitement palliatif des cancers surrénaliens” Rev        67- European Commission “Inventory of commu-
8- French Ministère de la santé et de la protection               Prescrire 1998; 18 (183): 264-266 + Prescrire Rédac-         nity and Member States’ incentive measures to aid
sociale “Plan national maladies rares 2005-2008”                  tion “Mitotane: forme pharmaceutique différente et           the research, marketing, development and avail-
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12 pages.                                                         39- Prescrire Editorial Staff “Zinc in Wilson’s disease”     - Hypertension artérielle pulmonaire: par voie orale,
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diseases in the EU” September 2005: 19 pages.                     Public Assessment Report (revision 2) - Scientific dis-
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13- Académie nationale de pharmacie “Sur la mise                  cussion-Busilvex°”: 33 + 10pages; posted on the EMEA
à disposition de médicaments orphelins destinés aux               website on 22 June 2006.

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