EU/3/01/020: Orphan designation for the treatment of patent ductus arteriosus

Patent ductus arteriosus (PDA) is a heart disease where the ductus arteriosus fails to close at birth. The pulmonary artery is a blood vessel that transports blood from the heart to the lungs. The aorta is a blood vessel that transports blood from the heart out to the rest of the body. In the womb, the baby gets its oxygen from the mother across the placenta (organ joining the mother and baby during pregnancy). The ductus arteriosus is the passageway that helps the distribution of oxygen from the mother to the baby's organs and allows blood flow to avoid the lungs.

In most babies, the ductus arteriosus closes within a few hours of birth. When the ductus arteriosus stays open (patent) after birth, blood travels in the wrong direction between the aorta and pulmonary artery. The abnormal blood flow patterns across the ductus may lead to heart failure, pulmonary (lung) hypertension (high blood pressure) and an increased risk of bacterial infection of the heart and ductus itself. The infection, or rupture of the ductus, may be life threatening.

Symptoms vary with the size of the ductus and the amount of blood that flows through it. If the ductus is small, there may be no symptoms. When symptoms occur they include; rapid breathing, increased work to breathe, getting tired quickly, poor growth, respiratory infection (e.g. cold).

At the time of designation, patent ductus arteriosus affected approximately 2.13 in 10,000 people in the European Union (EU). This was equivalent to a total of around 81,000 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: For the purpose of the designation, the number of patients affected by the condition is estimated and assessed on the basis of data from the European Union.
At the time of designation, this represented a population of 378,800,000 (Eurostat 2001).

Current treatment of patent ductus arteriosus comprises two steps. The first is medicinal treatment with an anti-inflammatory drug administered intravenously. The second step is surgical ligation (connection) of the ductus, if the medicinal treatment has failed. One product with anti-inflammatory activity was authorised for the condition in several Member States of the Community at the time of submission of the application for orphan drug designation.

Satisfactory argumentation has been submitted by the sponsor to justify the assumption that ibuprofen might be of potential significant benefit for the treatment of patent ductus arteriosus. The assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Ibuprofen is an anti-inflammatory drug which closes the ductus by inhibiting the production of prostaglandin. Prostaglandins are a class of hormone-like (chemical messenger) lipids (fats) present in tissues and bodily fluids. They may be involved in processes such as pain, inflammation and kidney function and affect blood pressure and smooth muscle (muscle that performs automatic tasks such as opening/closing blood vessels) activity.

The evaluation of the effects of ibuprofen in experimental models was ongoing.

At the time of submission of the application for orphan designation, no clinical trials in patients with patent ductus arteriosus were initiated.

Ibuprofen for intravenous formulation was not marketed anywhere worldwide for patent ductus arteriosus, at the time of submission.

Orphan designation of ibuprofen was granted in the United States in 1996 for patent ductus arteriosus.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 19 December 2000 recommending the granting of this designation.

Update: Ibuprofen (Pedea) has been authorised in the EU since 29 July 2004 for treatment of a haemodynamically significant patent ductus arteriosus in preterm newborn infants less than 34 weeks of gestational age.

• the seriousness of the condition;
• the existence of alternative methods of diagnosis, prevention or treatment;
• and either the rarity of the condition (affecting not more than five in 10,000 people in the Community) or the 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 the quality, safety and efficacy is necessary before a product can be granted a marketing authorisation.