EU/3/05/296: Orphan designation for the treatment of congenital adrenal hyperplasia

Congenital adrenal hyperplasia is an inherited condition that is present from birth and causes a diffuse enlargement of the adrenal glands. The adrenal gland consists of two small glands that are located above the kidneys, in the abdomen. The outer wall (cortex) of the adrenal gland secretes important substances, so-called steroid hormones. Steroid hormones include sex hormon'es and hormones used to control minerals and sugar in the body. These include cortisol, aldosterone and dehydroepiandrosterone. The formation and activation of these hormones depends on certain specific proteins (enzymes). The lack or malfunctioning of one of these enzymes, due to a genetic defect, will result in the blocking of the production of cortisol and aldosterone from the adrenal gland. This will then lead to an overproduction of male sex hormones.

Congenital adrenal hyperplasia is chronically debilitating. The metabolism of salt and water is disturbed causing dehydration, low blood pressure and loss of weight. The affected individuals may also develop excessive pigmentation in the skin. In boys, the syndrome produces early development of masculine characteristics and, in girls, it may lead to enlargement of the genital tract, lack of menstruation, deep voice and excessive hair (this phenomenon is called “virilisation”). In both sexes, the syndrome may result in short stature.

At the time of designation, congenital adrenal hyperplasia affected not more than 1 in 10,000 people in the European Union (EU). This was equivalent to a total of not more than 47,000 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 (EU 28), Norway, Iceland and Liechtenstein. This represents a population of 512,900,000 (Eurostat 2015).

Several products to treat congenital adrenal hyperplasia have been authorised. In particular, various steroid hormones can be used to replace those which are insufficiently produced by the adrenal gland. Hydrocortisone (modified release tablet) might be of potential significant benefit for the treatment of congenital adrenal hyperplasia because it is designed to mimic more closely the level of cortisol in the body. It may improve patient's acceptance of the treatment and prevent problems of masculinisation (or virilisation), infertility and excess steroid treatment. This assumption will have to be confirmed at the time of marketing authorisation. This will be necessary to maintain the orphan status.

Hydrocortisone (also known as cortisol) is the main steroid hormone secreted by the adrenal gland. Hydrocortisone (modified release tablet) is expected to replace natural the cortisol that is missing due to the congenital adrenal hyperplasia, and this may help to treat the symptoms of the disease.

At the time of submission of the application for orphan designation, no clinical trials in patients with congenital adrenal hyperplasia were initiated.

This specific formulation of hydrocortisone (modified release tablet) was not authorised anywhere worldwide for congenital adrenal hyperplasia or designated as orphan medicinal product elsewhere for this condition, at the time of submission.

In accordance with Regulation (EC) No 141/2000 of 16 December 1999, the COMP adopted a positive opinion on 15 June 2005 recommending the granting of this designation.

• 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 Community) 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.