WRITTEN QUESTION E-2144/01

by Jo Leinen (PSE) to the Commission

(18 July 2001)

Subject: Orphan Drug Directive - marketing authorisation for the treatment of Fabry'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'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 positive opinion 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 surrogate markers. 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 surrogate marker. This latter fact has also been stated by the company itself as well as its principal investigator.

1. How can a product receive a positive opinion for marketing authorisation in Europe, based on non-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?

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 exceptional circumstances 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.

3. The Commission received a position paper entitled the Application of orphan drug legislation from 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(6) concerning the two medicinal products which are the subject of this question. The relevance of surrogate markers with respect to an individual marketing authorisation application is a scientific matter which must be considered by the relevant scientific body responsible for the examination of a specific application, in this case the Committee for Proprietary Medicinal Products.

4. Numerous products for both rare and less rare diseases have been granted marketing authorisations 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.

(6) OJ L 18, 22.1.2000.