EU/3/06/372

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Orphan designation

On 22 May 2006, orphan designation (EU/3/06/372) was granted by the European Commission to DuoCort AB, Sweden, for hydrocortisone (modified-release tablet) for the treatment of adrenal insufficiency.

The sponsorship was transferred to DuoCort Pharma AB, Sweden, in November 2008 and subsequently to ViroPharma SPRL, Belgium, in February 2012.

What is adrenal insufficiency?

The adrenal gland consists of two small parts that are located above the kidneys, in the abdomen. The outer wall (cortex) of the adrenal gland secretes important steroid hormones. These include cortisol, aldosterone and dehydroepiandrosterone. Adrenal insufficiency is a rare disease that occurs when the adrenal glands do not produce enough of these hormones. Patients affected by this disease suffer of weight loss, muscle weakness, fatigue, low blood pressure, and sometimes darkening of the skin. Adrenal insufficiency can also cause irritability and depression. Some patients experience reduced general health and impaired sexuality. Because the symptoms worsen slowly, they are usually ignored until a stressful event like an illness or an accident causes them to become worse. This can develop into acute adrenal insufficiency ('Addisonian crisis'), which is life-threatening.

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

At the time of designation, adrenal insufficiency affected less than 4.5 in 10,000 people in the European Union (EU). This is equivalent to a total of fewer than 211,000 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 25), Norway, Iceland and Liechtenstein. At the time of designation, this represented a population of 468,900,000 (Eurostat 2006).

What treatments are available?

Several products to treat adrenal insufficiency have been authorised, including hydrocortisone, oral tablets administered in two or three daily doses. In particular, various steroid hormones can be used to replace those that are insufficiently produced by the adrenal gland.

Hydrocortisone (modified-release tablet) might be of potential significant benefit for the treatment of adrenal insufficiency, because it is designed to mimic more closely the natural level of cortisol in the body, which has a variable profile over the day. In particular, it may improve the early morning fatigues and the patient’s compliance to the treatment since it would be a single administration per day. This assumption 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?

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

What is the stage of development of this medicine?

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

This specific formulation of hydrocortisone (modified-release tablet) was not authorised anywhere worldwide for adrenal insufficiency 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 5 April 2006 recommending the granting of this designation.

Update: Hydrocortisone (modified-release tablet) (Plenadren) was authorised in the EU on 3 November 2011 for treatment of adrenal insufficiency in adults.

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 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.

Key facts

Product details for <p>Hydrocortisone (modified-release tablet)</p>
Active substanceHydrocortisone (modified-release tablet)
Medicine NamePlenadren
Disease/conditionTreatment of adrenal insufficiency
Date of decision22/05/2006
OutcomePositive
Orphan decision numberEU/3/06/372

Review of designation

During its meeting of 21 to 23 March 2016, the Committee for Orphan Medicinal Products (COMP) assessed whether Plenadren (hydrocortisone) still met the criteria for orphan designation as there appeared to be an increase in the prevalence of the condition.1 Plenadren has been authorised in the European Union for the treatment of adrenal insufficiency since 3 November 2011. At the time, because Plenadren met the criteria for orphan designation, it was granted 10 years of market exclusivity in the EU.2

A Member State can ask that this period of market exclusivity be reduced to 6 years if at the end of 5 years the criteria for orphan designation no longer apply and the medicine is sufficiently profitable.

At the request of the United Kingdom, the COMP therefore reviewed the criteria for orphan designation for Plenadren. The Committee looked at the seriousness and prevalence of the condition and the existence of other methods of treatment. As other methods of treatment are authorised in the European Union (EU), the COMP also considered whether the medicine is of significant benefit to patients with adrenal insufficiency. As these criteria continue to be met, the COMP recommended that the 10-year period of market exclusivity granted to Plenadren in 2011 for the treatment of adrenal insufficiency should not be reduced.

For more information about the original review at the time of initial marketing authorisation see:


1In accordance with Article 8(2) of Regulation (EC) No 141/2000.

2This means that in the 10 years after authorisation similar products for the same therapeutic indication cannot be placed on the market.

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

Plenadren is authorised in the EU for the treatment of adrenal insufficiency in adults. The product’s designated orphan indication is ‘treatment of adrenal insufficiency’.

The COMP concluded that there had been no change in the seriousness of the condition since the review of the designation at the time of marketing authorisation of Plenadren. Adrenal insufficiency remains a condition that is debilitating in the long term because of tiredness and weakness that affect quality of life. If left untreated the condition can be life threatening, as it can progress to adrenal crisis leading to shock and death.

Prevalence of the condition

The sponsor provided updated information on the prevalence of adrenal insufficiency based on data from the scientific literature.

On the basis of the information provided by the sponsor and the discussion within the COMP, the COMP concluded that the prevalence of adrenal insufficiency has increased to 4.85 people in 10,000 since its authorisation.* This still remains below the ceiling for orphan designation, which is 5 people in 10,000, and is equivalent to a total of around 249,000 people in the EU.


*At the time of authorisation, the estimated prevalence was 4.5 people in 10,000.

Existence of other satisfactory methods of treatment

At the time of this review, other treatments were authorised in the EU for the treatment of adrenal insufficiency, including hydrocortisone oral tablets administered in two or three daily doses, and synthetic glucocorticoids (steroid hormones).

Significant benefit over existing treatments

The COMP concluded that Plenadren remains of significant benefits for patients with adrenal insufficiency because based on clinical data its once-daily modified release formulation produces benefits in terms of body fat, control of blood sugar, and aspects of patients’ quality of life compared with existing treatments. This was considered a major contribution to patient care.

Conclusion

Based on the available data and the scientific discussion within the COMP, the COMP considered that Plenadren still meets the criteria for designation as an orphan medicinal product and that the period of market exclusivity for Plenadren should not be reduced.

Related information

Sponsor’s contact details

ViroPharma SPRL
Rue Montoyer 47
1000 Brussels
Belgium
Tel. +32 2747 0971
Fax +32 2747 0942
E-mail: john.watson@viropharma.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.