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Orphan Drugs – an Overview

17 th Jul Orphan Drugs – an Overview

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Orphan Drugs – an Overview

Executive Summary

Orphan medicinal products are used to diagnose, treat and prevent rare diseases.  A rare disease is defined as occurring in not more than 5 per 10,000 individuals in the European Union.  Because numbers are small (and therefore the potential market for a new drug to treat them is small), people who have rare diseases or disorders, have had little research attention in past decades. However in 2000 the European Union (EU) implemented Orphan Drug Regulation (EC) No 141/2000 to promote research and development of orphan medicines in the EU to reduce the disparity.

The purpose of this report is to provide a brief overview of orphan drugs describing:

–  What orphan designation is

–  The incentives of developing Orphan Medicinal Products

–  The application process to obtain Orphan Designation

  1. What are Orphan Medicinal Products?

Orphan medicinal products are used to diagnose, treat and prevent rare diseases.  The European Union (EU) implemented Orphan Drug Regulation (EC) No 141/2000 to promote research and development of orphan medicines in the EU.

  1. What is Orphan designation?

Article 3 of the Orphan Drug regulation defined two criteria for orphan disease designation (ODD) by the EU.  First, the prevalence of the life threatening or chronically debilitating disease should be not more than 5 in 10,000 and the revenue generated by medicines for such rare disease is less than the investment.  The second criteria being that no satisfactory medicinal product is available for diagnosis, treatment and prevention of a rare disease or if such an authorised product is available, the proposed medicinal product will offer significant benefit to the patients.

Application by persons or companies (sponsors) for orphan medicinal product designation could be submitted at any phase of the medicinal product development but must be before an application for a marketing authorisation is made.  No fee is charged for the designation procedure. An orphan designation for a medicinal product does not automatically qualify the product for marketing rights in the EU. A medicinal product, if conferred an orphan designation, still needs to meet the criteria of quality, safety and efficacy when an application for marketing authorisation is submitted to the European Medicines Agency (EMA).

  1. What are the incentives of developing an Orphan Medicinal Product?

The designation of a disease as an orphan disease not only allows for availability of treatment for patients suffering from them but also offers incentives to persons or companies involved in the development of orphan medicinal products.

–  10 years market exclusivity: Applied to all Orphan Medicinal Products with the exception of Paediatric Orphan Medicinal products which are granted 12 years market exclusivity: For 10/12 years after the approval the orphan medicinal product enjoys exclusive marketing rights in the EU. No other similar product which is a competition for the approved product can be placed on the market during this period.

–  Protocol assistance: EMA provides free scientific advice to sponsors during the development of the product and guidance in preparing the dossier to meet regulatory requirements in Europe.

–  Fee reduction or exemption: There is a reduction in fees charged for all types of centralised activities, including applications for marketing authorisation, inspections, variations and protocol assistance. The reduction amount is subject to the classification of the sponsor. Small Medium Enterprise (SME) sponsors benefit from 100% fee reduction (in other words- no fee) for protocol assistance, initial marketing authorisation application and post authorisation applications during the first year of being granted marketing authorisation. Whereas Non-SMEs only benefit from a 75% fee reduction from protocol assistance and a 10 % fee reduction from initial marketing authorisation applications. (EMA/317270/2014)

–  All Orphan designated medicines must apply via the centralised procedure in the European Union. This allows the medicinal product to be marketed in all EU members of states with one application.

–  EU funded research: The sponsors developing the orphan medicinal products might qualify for EU grants, programmes and initiatives of member states that support research and development.

  1. To Whom are the applications for obtaining Orphan Medicinal Product designation submitted?

The applications to obtain orphan designation for the medicinal product are submitted to the EMA. The agency accepts only electronic applications for orphan drug designation. These applications are reviewed by the Committee for Orphan Medicinal Products (COMP) that issues its opinion on whether the medicinal product meets the criteria for orphan designation.

  1. Procedure to Obtain Orphan Designation (Figure 1)

1) If the medicinal product has not been granted an orphan designation by the FDA, then the sponsor can seek orphan designation from the FDA and EMA by using a common application form.

2) The submission of the application is done electronically by the deadlines published by the EMA on their website

3) Once submitted, the applications are validated by the EMA. If there are validation issues, the sponsors are issued a letter and the information is requested within a three month time limit. If sponsors fail to send their response to these validation issues, they are requested to resubmit a new complete application.  The validation date is considered to be the first day of the procedure to obtain the orphan designation for the proposed medicinal product.

4) The applications are then evaluated by COMP. Before day 90, the final opinion on the medicinal product is determined and published on the EMA website.

5) Negative opinion prior to appeal: In case the final opinion of COMP is likely to be negative, a list of questions are prepared by COMP and forwarded to the sponsor. The sponsor may be invited to provide an oral explanation before the COMP prior to adoption of the opinion.

6) Once the opinion is adopted by the COMP, the EMA will forward the opinion to the sponsor and the European Commission. If the opinion is negative it is only sent to the sponsor.

7) Appeal post adoption of opinion: If the opinion is negative the sponsor’s intention to appeal should be communicated to the EMA. The sponsor may be able to schedule a meeting with the agency prior to submission of any appeal documentation.  The grounds for appeal should be sent to the agency within 90 days of the receipt of the opinion. The grounds of appeal received from the sponsor are forwarded to COMP and are considered for the revision of opinion in the next COMP meeting. The appeal process formally starts at this meeting and the sponsor is invited for oral explanation in the next COMP meeting.

8) Once the opinion is positive and adopted by COMP, the EMA will forward the opinion to the European Commission and to the sponsor. The Commission adopts a decision within 30 days of the receipt of the opinion.

9) The decision of the European Commission is then notified to the sponsor and communicated to the EMA as well as the member states of the EU. The public summary of the opinion is published on the EMA website.

10) Once the medicinal product has been granted an orphan designation, the designated medicinal product is included in the Community Register of Orphan Medicinal Products.

Figure 1. Procedure to Obtain Orphan Designation



















  1. What leads to a successful application?

–  Presubmission Meetings: A meeting between sponsors and the EMA at least two months before submitting the actual application is helpful in answering questions regarding the application and increases the likelihood of a successful application. This meeting is free of charge and the minutes of the meeting can be taken and later approved by the EMA.

–  Application Form: Ensure completion of the application form for orphan drug designation by including full copies of literature references according to the guideline (ENTR/6283/00).

–  Important Sections of the Application:

a) Medical Plausibility

 Medical plausibility should include the rationale behind the use of the medication and justification for restricting the medication to a subset of the population with the proposed orphan indication. A description of the medicinal product and its mechanism of action should be detailed in this section. If the orphan indication is a subset of a particular condition, the criteria used for defining the subset of population should be described. It should be established whether the proposed medicinal product is used in the treatment, prevention and diagnosis of a life threatening or chronically debilitating condition. This is an important criteria in Article 3.1 of Regulation (EC) No 141/2000 for the medicine to be granted an orphan designation.  Any preliminary data, whether it is clinical or preclinical, is required to support the application of the products under development.  A concept for an orphan medicinal product not supported by preliminary studies is not considered a good justification by COMP to confer orphan designation to the medicinal product. Further guidelines for this section can be found on the EMA website (EMA/COMP/15893/2009, ENTR/6283/00 Rev 4).

b) Justification of the life-threatening or debilitating nature of the condition

It should be established by literature or epidemiological data that the proposed orphan indication is a life threatening or chronically debilitating condition and not merely inconvenient for patients.

c) Prevalence of the proposed orphan indication

This section should clearly demonstrate and conclude that the point prevalence of the proposed orphan disease is not more than 5 in 10,000 in the Community at the time of the application, for it to be a rare disease.  The requirement for what is reported in the prevalence section depends on whether the intended medicinal product is used for treatment or for diagnosis/prevention of the orphan indication. The products used for diagnosis and prevention of the proposed orphan indication need to demonstrate that not more than 5 in 10,000 are receiving the preventive treatment or diagnostic test. In comparison to that the medicinal products for treatment of the prevalence is calculated on the basis of people suffering from the condition.

To arrive at the figure for point prevalence one would need to divide the number of people suffering from the proposed orphan indication at the time of the application by the population of the Community at that time.  Even if the disease affects a subset of the population, the prevalence of the disease in the EU should be calculated in the population which includes the population of EU member states as well as Iceland, Liechtenstein and Norway. For acute conditions, yearly incidence at the time of the application will be more relevant than the point prevalence of the condition.

The details required to calculate prevalence varies from condition to condition. If the prevalence of the condition, as shown by the majority of the epidemiological data, is far below the limit of 5 in 10,000 people, then the application does not require minute details used to estimate the prevalence data.  On the other hand, if the prevalence is close to the threshold criteria of 5 in 10,000 people, then more details of the methodology used to estimate the prevalence data are required.

The typical sources of prevalence data include epidemiological data, community databases, peer reviewed journal articles, registries of rare disease or patient organisations and statements from experts. The lack of data for some rare conditions might make this section challenging.

The strategy for identification of prevalence data and to address the possibility of bias in selection, a discussion should be provided. The assumptions made in the absence of up to date references and when extrapolating disease prevalence in a particular country to other countries in the EU, should be clearly stated. The studies should be presented critically and clearly in a tabular format with all the relevant information including characteristics of the study population. The assumptions, methods and results used to calculate the prevalence of the disease at the time of the application must be clearly presented. After presenting the main results for the prevalence data the sponsor should include a conclusion on the prevalence of the orphan indication in the population. The detailed guidelines about this section of the application can be found on the EMA website (COMP/436/01).

d) Justification of Significant Benefit:

This section of the application describes whether the drug provides significant benefit over the existing medications for diagnosis, prevention or treatment of a disease.  The medicinal product should offer benefits in terms of efficacy or safety or a more favourable pharmacokinetic profile over the available medications for the orphan indication. A comparison should be made between the available treatments and the proposed medicinal product if there are methods available for treatment, diagnosis or prevention of indicated orphan indication.

Usually applications for designation of orphan medicinal products are made while they are being developed; in which case the comparative data between existing and proposed medication might not be available. A comparison of the existing or available methods and the potential benefits of the proposed medication might be made.  In the absence of clinical trial data, preclinical data, if available, should be provided in comparison to the existing or available methods. However, the assumed benefits should be based on sound pharmacological principles and supported by appropriate references.

The application, if made on the basis of improved safety profile of the proposed medicinal product, should provide clinical data or in some exceptions pharmacological properties of the medicinal product to support the application. The safety issues with existing or available medicinal products for the orphan indication must be observed or documented rather than being theoretical in nature.

Besides the fact that the proposed medication is superior to the available medications in terms of efficacy or safety, the sponsor can also claim that the medicinal product makes a major contribution to patient care. Examples of such claim can be a convenient mode of administration of medication to improve patient compliance or improved availability of medicines for the patients with orphan indication. All the claims for significant benefit are subsequently scrutinised by the EMA during the application for marketing authorisation. (EMA/COMP/15893/2009)

  1. Conclusion

Orphan medicinal products have been historically neglected by mainstream pharmaceuticals, given the limited patient population affected.  However, from 2000 when the Orphan Regulation was adopted, to the end of 2016, 2,714 applications for orphan medicinal product designation have been reviewed by COMP. Of these 2,714 applications 1,827 (67%) have been successfully granted an orphan medicinal product designation. The prevalence of the majority of conditions which have been granted orphan designation was less than 1 in 10,000 people in the EU. These figures are for up to the end of 2016 and numbers are likely to keep increasing. Up to the end of 2016, 146 medicinal products with orphan designation have been granted marketing authorisations in the EU.

Oncology is the leading condition for which orphan designation and marketing authorisations have been granted. A possible reason for this intense focus on oncology within the pharmaceutical industry is the underlying genetic aberration of oncology, which often provides the signature for disease identification. Additionally, there have been recent developments in the use of customised or precision medicine within the oncology field.

Figure 4 shows the Compound Annual Growth Rate (CAGR) of the Orphan Drug Market from 2000 to 2022. It suggests the CAGR of launched orphan drugs will outshine that of non-orphan drugs over the next 30 years.

This growth within the Orphan Medicinal Market verifies that orphan regulation has successfully allowed the development of medicinal products for rare diseases that otherwise would not have been possible without the incentives offered to the companies developing orphan medicinal products.

Thus the Orphan Regulation has successfully allowed the development of medicinal products for rare diseases that otherwise would not have been possible without the incentives offered to the companies developing orphan medicinal products.

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Figure 2 Market Authorisation for Orphan Medicines by Therapeutic Area


Figure 3 Total Number of Authorised Orphan Drugs with European Market Authorisation and Orphan designation


Figure 4 Evaluate Pharma Report on the Growth of Orphan Drugs  



Resources: 1 , 2, 3, 4, 5, 6, 7

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