EU/3/03/140

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Orphan designation

On 17 April 2003, orphan designation (EU/3/03/140) was granted by the European Commission to Chiron Corporation Limited, United Kingdom, for tobramycin (inhalation powder) for the treatment of Pseudomonas aeruginos a lung infection in cystic fibrosis. 

The sponsorship was transferred to Novartis Europharm Limited, United Kingdom, in October 2006.

What is Pseudomonas aeruginosa lung infection in cystic fibrosis?

Cystic fibrosis is a genetic disease. The genetic information that determines the characteristics of each individual is carried by genes located on structures called chromosomes. In humans, each cell has 23 pairs of chromosomes. For each pair one chromosome is inherited from the mother and the other from the father. Cystic fibrosis is caused by abnormalities of a specific gene, called CFTR, carried by the 7th pair of chromosomes. The CFTR gene is responsible for the production of a protein that regulates outflow of water and salts (like chloride) from cells that cover internal and external surfaces of the body, the so-called epithelial cells. Cystic fibrosis appears only when the CFTR is abnormal on both chromosomes of the 7th pair. The defective transport of water and salts due to the lack of the regulatory protein results in the thickening of the secretions in several organs (e.g. lungs, pancreas). This leads to chronic infection of the lungs and chronic inflammation (a response to the injury caused to the tissue). Pseudomonas aeruginosa is a species of bacteria (micro-organisms that can cause certain types of infections). Chronic infection of the lung with Pseudomonas aeruginosa is a typical feature of cystic fibrosis. It can induce damage to the lung tissue and respiratory insufficiency, which is life threatening.

What is the estimated number of patients affected by the condition?

At the time of designation, Pseudomonas aeruginosa lung infection in cystic fibrosis affected approximately 1.3 in 10,000 people in the European Union (EU)*. This is equivalent to a total of around 49,000 people, and is below the ceiling for orphan designation, which is 5 people in 10,000. This is based on the information provided by the sponsor and the knowledge of the Committee for Orphan Medicinal Products (COMP).

*Disclaimer: The number of patients affected by the condition is estimated and assessed for the purpose of the designation, for a European Community population of 377,000,000 (Eurostat 2001) and may differ from the true number of patients affected by the condition. This estimate is based on available information and calculations presented by the sponsor at the time of the application.

What treatments are available?

Pseudomonas aeruginosa lung infection in cystic fibrosis is treated mostly with antibiotic (drugs that kill micro-organisms) therapy administered by a variety of routes, oral, intravenous and as an aerosol via nebulisation. Several antibiotics had been authorised for the condition in some countries in the Community, at the time of submission of the application for orphan designation. Satisfactory argumentation has been submitted by the sponsor to justify the assumption that tobramycin (inhalation powder) might be of potential significant benefit for the treatment of Pseudomonas aeruginosa lung infection in cystic fibrosis, particularly in regards to a contribution to patient care. The assumption of benefit is yet to be validated and will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

How is this medicine expected to work?

Tobramycin is an antibiotic produced by certain strains of bacteria with activity against a wide range microorganisms including Pseudomonas aeruginosa. The sponsor has developed a formulation for dry powder inhalation to be administered with a commercial device. It acts by disrupting protein synthesis and this kills the microorganisms.

What is the stage of development of this medicine?

The evaluation of the effects of tobramycin (inhalation powder) in experimental models is ongoing.

At the time of the submission of the application for orphan designation clinical trials with tobramycin inhalation powder in cystic fibrosis patients with Pseudomonas aeruginosa lung infection had not been initiated.

Tobramycin inhalation powder was not marketed anywhere worldwide for the condition, at the time of submission and has not been submitted or approved for a marketing authorisation in any country.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 7 February 2003 recommending the granting of this designation.

Update: tobramycin (inhalation powder) (Tobi Podhaler) has been authorised in the EU since 20 July 2011 for the suppressive therapy of chronic pulmonary infection due to Pseudomonas aeruginosa in adults and children aged 6 years and older with cystic fibrosis.

Opinions on orphan medicinal product designations are based on the following three criteria:
  • the seriousness of the condition;
  • the existence of alternative methods of diagnosis, prevention or treatment;
  • either the rarity of the condition (affecting not more than 5 in 10,000 people in the EU) or insufficient returns on investment.

Designated orphan medicinal products are products that are still under investigation and are considered for orphan designation on the basis of potential activity. An orphan designation is not a marketing authorisation. As a consequence, demonstration of quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.

Key facts

Product details for <p>Tobramycin (inhalation powder)</p>
Active substanceTobramycin (inhalation powder)
Medicine NameTobi Podhaler
Disease/conditionTreatment of Pseudomonas aeruginosa lung infection in cystic fibrosis
Date of decision16/03/2003
OutcomePositive
Orphan decision numberEU/3/03/140

Review of designation

During its meeting of 6-7 October 2010, the Committee for Orphan Medicinal Products (COMP) reviewed the designation EU/3/03/140 for Tobi Podhaler (tobramycin) as an orphan medicinal product for the treatment of Pseudomonas aeruginosa lung infection in cystic fibrosis. 

The COMP assessed whether, at the time of marketing authorisation, the medicinal product still met the criteria for orphan designation. The Committee looked at the seriousness and prevalence of the condition, and the existence of other satisfactory methods of treatment. 

As other satisfactory methods of treatment for patients with this condition are authorised in the European Union (EU), the COMP also looked at the significant benefit of the product over existing treatments. The COMP recommended that the orphan designation of the medicine be maintained.

Life-threatening or long-term debilitating nature of the condition

The Committee for Medicinal Products for Human Use (CHMP) recommended the authorisation of Tobi Podhaler for:

‘the suppressive therapy of chronic pulmonary infection due to Pseudomonas aeruginosa in adults and children aged six years and older with cystic fibrosis’.

This falls within the scope of the product’s designated orphan indication, which is: ‘treatment of P. aeruginosa lung infection in cystic fibrosis’.

The COMP concluded that there had been no change in the seriousness of the condition since the orphan designation in 2003. P. aeruginosa lung infection in cystic fibrosis remains a condition that is debilitating in the long term and life threatening, particularly because of the damage to the lung tissue that leads to progressive respiratory insufficiency.

Prevalence of the condition

On the basis of the information provided by the sponsor and the knowledge of the COMP, the COMP concluded that the prevalence of P. aeruginosa lung infection in cystic fibrosis remains below the threshold for orphan designation, which is 5 people in 10,000. At the time of the review of the orphan designation, the prevalence was still estimated to be approximately 1.3 people in 10,000. This is equivalent to a total of around 66,000 people in the EU.

Existence of other satisfactory methods of treatment

At the time of the review of the orphan designation, lung infections in patients with cystic fibrosis were mainly treated with antibiotics. These included tobramycin, an antibiotic that belongs to the group ‘aminoglycosides’. Tobramycin was authorised as Tobi in several European Member States for the long-term treatment of P. aeruginosa infections in cystic fibrosis. Tobi is available as a solution for inhalation to be used with a nebuliser (a device that changes the solution into an aerosol that the patient can inhale).

Since the orphan designation of Tobi Podhaler, Cayston (aztreonam) has also received marketing authorisation in the EU for the suppressive therapy of chronic pulmonary infections due to P. aeruginosa in patients with cystic fibrosis aged 18 years and older. The active substance in Cayston, aztreonam, belongs to a different class of antibiotics, beta-lactams.

In addition, other medicines used to treat the lung symptoms of cystic fibrosis included bronchodilators (medicines that help open up the airways in the lungs) and mucolytics (medicines that help to dissolve the mucus). Patients were also advised to exercise and have physiotherapy.

Significant benefit over existing treatments

The COMP noted that Tobi Podhaler was at least as efficacious as Tobi in clinical trials in patients with cystic fibrosis aged six years and over. The COMP concluded that the claim of a significant benefit of Tobi Podhaler over Tobi is justified on the basis of the added convenience in the use of the medicine. Due to its formulation, Tobi Podhaler can be inhaled using a hand-held device, which allows a shorter inhalation time of 5.6 min compared with 19.7 min with Tobi. In addition, the improved portability of the device, which weighs 20 g and does not need electricity, is considered to be a major contribution to patient care.

When comparing Tobi Podhaler with Cayston, as well as with other antibiotics, the COMP noted that Tobi Podhaler has a different mechanism of action. The claim of significant benefit is justified on the basis of it being a complementary therapeutic option to treat P. aeruginosa infection in cystic fibrosis.

Therefore, although other satisfactory methods for the treatment of this condition have been authorised in the EU, the COMP concluded that Tobi Podhaler is of significant benefit for patients affected by P. aeruginosa lung infection in cystic fibrosis.

Conclusions

Based on the data submitted and the scientific discussion within the COMP, the COMP considered that Tobi Podhaler still meets the criteria for designation as an orphan medicinal product and that the medicine should remain in the Community Register of Orphan Medicinal Products.

Sponsor’s contact details:

Novartis Europharm Limited
Wimblehurst Road
Horsham
West Sussex
RH12 5AB
United Kingdom
Telephone: +44 14 03 27 28 27
Telefax: +44 14 03 32 30 60
E-mail: carol.beauchamp@pharma.novartis.com

Patients' organisations:

For contact details of patients’ organisations whose activities are targeted at rare diseases see:

  • Orphanet, a database containing information on rare diseases which includes a directory of patients’ organisations registered in Europe.
  • European Organisation for Rare Diseases (EURORDIS), a non-governmental alliance of patient organisations and individuals active in the field of rare diseases.