WRITTEN QUESTION E-2144/01 by Jo Leinen (PSE) to the Commission. Orphan Drug Directive - marketing authorisation for the treatment of Fabry's Disease.
Date: 2001-07-18
Institutions: European Parliament, Provisional data
Subjects: Community certification, market approval, medicinal product, pharmaceutical legislation

14.2.2002

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Official Journal of the European Communities

C 40 E/199

they are already
Regarding new drugs already in circulation outside the Community, the fact
authorised in another third country does not imply that the EMEA or the reference Member State in the
context of the decentralised procedure are obliged to proceed to their approval. The evaluation of new
drugs has to be considered on a case by case basis and will only be essentially accelerated if those fall
within the categories for which the (cid:145)fast-track(cid:146), conditional or (cid:145)compassionate use(cid:146) authorisations have been
proposed.

that

(2)
(3)

(1) Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the authorization
and supervision of medicinal products for human and veterinary use and establishing a European Agency for the
Evaluation of Medicinal Products (OJ L 214, 24.8.1993).
Instituted by Regulation (EEC) No 2309/93.
From 1995 to May 2001, 171 authorisations have been granted under this procedure for medicinal products for
human use and 26 for medicinal products for veterinary use.
(cid:145)Evaluation of the operation of Community procedures for the authorisation of medicinal products(cid:146), Evaluation
carried out on behalf of the European Commission, Cameron McKenna (cid:129) Andersen Consulting, available on http://
pharmacos.eudra.org.

(4)

(5) Council Directive 89/105/EEC relating to the transparency of measures regulating the pricing of medicinal products
for human use and their inclusion in the scope of national health insurance systems (called the (cid:145)transparency(cid:146)
directive) (OJ L 40, 11.2.1989).

(2002/C 40 E/216)

WRITTEN QUESTION E-2144/01

by Jo Leinen (PSE) to the Commission

(18 July 2001)

Subject: Orphan Drug Directive (cid:129) marketing authorisation for the treatment of Fabry(cid:146)s Disease

When drafting and discussing the Orphan Drug Directive, nobody apparently considered the possibility
that two products for the same indication could be submitted at the same moment. This however seems to
have happened in July 2000 for Fabry(cid:146)s Disease. Both products received from the COM (Committee for
Orphan Medicines) an orphan drug status. Moreover, they were both given by the CPMP (Committee for
Proprietary Medicinal Products) a (cid:145)positive opinion(cid:146) for granting marketing authorisation on 29 March
2001. Since Directive EC65/65, the criteria on which a pharmaceutical product has to be evaluated for
marketing authorisation are quality, safety and efficacy. The efficacy of a pharmaceutical product has to be
proven on the basis of clinical studies with validated endpoints for clinical benefits, and not based on non-
validated so-called (cid:145)surrogate markers(cid:146). In this case, one product, Replagal, showed clinical benefits by
reducing pain, improved renal function and a reduction of the cardiac mass. Another product, Fabrazyme,
has not been able to document clinical benefits, but only effect on a non-validated (cid:145)surrogate marker(cid:146). This
latter fact has also been stated by the company itself as well as its principal investigator.

How can a product receive a positive opinion for marketing authorisation in Europe, based on non-
1.
validated surrogate markers, when it has failed to demonstrate clinical benefits? Even more remarkable,
how could this happen when the other product has documented significant clinical benefits, with a
probably better safety profile?

2.
How can it be in the interests of patients with a debilitating orphan disease to be treated with a
product approved on a non-validated surrogate marker, when they have to wait for the outcome of future
studies to know if there may be a clinical benefit, especially in the case where another product is
scientifically proven to have clinical benefits?

3. Why has the letter from TKT Europe 5S of December 21 2000, dealing with this matter and sent to
your Directorate c/o Pharmaceuticals and Cosmetics Unit, never officially been answered, with regard to
the use of non-validated surrogate markers? One might assume that the transparency of the process could
be served with an early answer?

4.
Does this positive opinion from the CPMP for a product with effects only on a non-validated
surrogate marker, reflect a shift in policy on allowing marketing authorisations in Europe, and if so, why
has this not been publicly communicated to the industry and medical community?

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Official Journal of the European Communities

EN

14.2.2002

Answer given by Mr Liikanen on behalf of the Commission

(12 October 2001)

Regulation (EC) No 141/2000 of the Parliament and of the Council of 16 December 1999 on Orphan
Medicinal Products (1) came into force on 28 April 2000. The Regulation aims to provide incentives to
encourage the research and development and availability of medicines to treat patents suffering from rare
diseases, diseases which affect less than 5 per 10 000 of the population in the Community and for which
no satisfactory treatment exists. Fabry disease is one such disease, occurring in approximately one in every
400 000 of the population. The disease is an inherited metabolic disorder due to an enzyme deficiency
which causes the accumulation of certain sphingolipids, resulting in pain, damage in the kidney and other
organs and a greatly shortened life expectancy.

Council Directive 65/65/EEC of 26 January 1965 on the approximation of provisions laid down by Lax,
Regulation or Administrative Action relating to proprietary medicinal products (2) requires all medicinal
products to be evaluated on the basis of a dossier prepared by a company and which must provide, inter
alia, the results of physico-chemical, biological or microbiological tests, pharmacological and toxicological
tests and clinical trials. The clinical trials should be designed to determine the efficacy and safety of the
medicinal product under normal conditions of use. With respect to certain therapeutic indications, and in
particular for rare diseases, where the indications for which the product is intended are encountered so
rarely that the applicant cannot reasonably be expected to provide as comprehensive evidence as would
normally be required, marketing authorisations may be granted in exceptional circumstances (Article 13(2)
of Council Regulation (EEC) No 2309/93 of 22 July 1993 laying down Community procedures for the
authorisation and supervision of medicinal products for human and veterinary use and establishing a
European Agency for the Evaluation of Medicinal Products (3) as amended (4) and part 4G of the annex to
Council Directive 75/318/EEC of 20 May 1975 on the approximation of the laws of Member States
relating to analytical, pharmaco-toxicological and clinical standards and protocols in respect of the testing
of proprietary medicinal products (5)). Marketing authorisations granted in exceptional circumstances are
subject to certain specific obligations which are reviewed annually. In the case of the two medicinal
products in question, positive scientific opinions have been given on the basis of this provision.

1.
Each marketing authorisation is assessed independently on the basis of its own merits as detailed in
the clinical documentation provided in the dossier. It is not uncommon for marketing authorisations to be
granted on the basis of surrogate endpoints, in particular where the disease concerned has a long evolution
and a long-term outcome.

In the case of Fabry disease, there is a characteristic histopathological finding due to the accumulation of
sphingolipids which is linked with morbidity and mortality. Reduction of this accumulation in patients
indicates potential long-term clinical improvement. The use of sphingolipid accumulation in the kidney as
an endpoint was therefore considered scientifically acceptable based on the pathophysiology of this very
rare and serious disease and the causal link between the accumulation of sphingolipids with morbidity and
mortality.

The pathogenesis of Fabry disease is based on an enzymatic deficiency and there is therefore a strong
pharmacological rationale that administration of the enzyme to the patients will be of potential clinical
benefit to the patients.

Although the clinical development plans, including the endpoints used for both Fabrazyme and Replagal
were different, both products were able to provide data which was considered by the competent scientific
committee, the Committee for Proprietary Medicinal Products, to be indicative of long-term clinical
benefits. Regarding their safety profiles,
it was likewise concluded that both products had acceptable
adverse events profile. Both products were considered according to the (cid:145)exceptional circumstances(cid:146)
provisions referred to above and both companies have been requested to submit additional clinical data as
part of their specific obligations.

2.
Fabry disease is a rare and debilitating disease for which currently no effective treatment is available.
The authorisation of two new treatments which have shown results indicative of long-term clinical
benefits, whether based on surrogate or other endpoints, is therefore expected to represent a major step
forward for patients suffering from this disease.

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Official Journal of the European Communities

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The Commission received a position paper entitled the (cid:145)Application of orphan drug legislation(cid:146) from
3.
Transkaryotic Therapies, Inc. (TKT) dated 21 December and a reply was sent on 31 January 2001. This
position paper has been considered with respect to the interpretation of Regulation (EC) No 141/2000 of
the Parliament and of the Council of 16 December 1999 on orphan medicinal products (1) concerning the
two medicinal products which are the subject of this question. The relevance of surrogate markers with
to an individual marketing authorisation application is a scientific matter which must be
respect
considered by the relevant scientific body responsible for the examination of a specific application, in this
case the Committee for Proprietary Medicinal Products.

Numerous products for both rare and less rare diseases have been granted marketing authorisations
4.
based on surrogate endpoints including products for the treatment of diabetes, hypertension, Gaucher
disease, and nephropathic cystinosis. For all medicinal products authorised on the basis of a scientific
opinion of the CPMP, (centrally approved products) a summary of the data which has been presented, and
the grounds on which the authorisation is based is published in the form of a European Public Assessment
Report (EPAR) following the grant of the marketing authorisation ensuring transparency of the decision
making process to all interested parties including the industry, the medical community and the general
public.

(1) OJ L 18, 22.1.2000.
(2) OJ B 22, 9.2.1965.
(3) OJ L 214, 24.8.1993.
(4) OJ C 335, 6.11.1997.
(5) OJ L 147, 9.6.1975.

(2002/C 40 E/217)

WRITTEN QUESTION E-2145/01

by Jeffrey Titford (EDD) to the Commission

(18 July 2001)

Subject: Public library subsidy

1.
Is the Commission aware that the European Union is complicit in an anti-competitive trading
situation because it has authorised only one commercial agent for the supply of its literature in the UK,
namely The Stationery Office (TSO)?

2.
Is it aware that it has created a monopoly situation in authorising only one agent (TSO) and that that
agent is the only mechanism through which libraries throughout the UK may claim a Public library
subsidy?

Is it aware that UK Government publications and the Public library subsidy for them are much more

3.
freely available?

4. What steps does the Commission propose to take to resolve the anti-competitive position it has
taken on the sale and distribution of its own literature?

Answer given by Mrs Reding on behalf of the Commission

(24 October 2001)

1.
The Commission and other European institutions as well as agencies sell their publications and other
information services (databases, document delivery, etc.) through a network of sales agents. This network is
managed by the Office for Official Publications of the European Communities (EUR-OP). Sales agents act
on the basis of a contract granting them non-exclusive rights to sell publications and/or other services to
any client anywhere. Any firm wishing to become a sales agent may sign a contract with EUR-OP. There
are currently more than 60 sales agents in the Member States, of which 19 sell paper publications only. In
the United Kingdom there are six agents: one sells books and electronic products, one is a data-base
gateway, one is a document delivery agent and three sell electronic products only.

EUR-OP also sells directly through the Internet (http//online.eur-op.eu.int).