The Rise of Orphan Drugs

Approvals for Orphan drugs have been on the increase within both the USA and EU ever since legislation was introduced in an attempt to stimulate research into rare diseases.  The 1983 Orphan Drug Act and EU Regulation 141/2000 provided a new product class to which pharmaceutical companies can apply for marketing authorisations.  Both the EMA and FDA has seen a sustained increase in applications.  Approximately 30% of all applications for new molecular entities within the USA are for Orphan drugs and the EMA has seen a 40% increase over the past few years.

What is an Orphan Drug?

For a drug to be classified as an orphan drug the disease it is being used to treat must be designated an orphan disease.  Within the EU an orphan disease is one which affects less than 1 in 2000 patients per year and this disease must be registered with the EMA in order to gain orphan status.  This application (or sponsorship) is submitted by a corporate body, an individual researcher or a combination of both.  The sponsorship details both the orphan disease and a proposed treatment and once granted by the committee of orphan medicinal products (COMP) the sponsorship lasts for 10 years.  Within that 10 year period is it normally assumed that an application for a marketing authorisation will be submitted.  Interestingly only the holder of the orphan designation (sponsorship) can be named as the MA holder on the MAA for the treatment specified within the orphan designation.  An example of an orphan designation can be found here.

There are also a number of incentives available for pharmaceutical companies to invest in the development of orphan drugs.  These include tax relief, reduced MA application fees and most importantly product exclusivity for 10 years.  Many of these drugs, such as enzyme replacement therapies are designed to be a chronic treatment thereby requiring the patient to be treated for life.  This will obviously help companies offset the reduced size of the target population.  

With England the frequently quoted limit for new treatments to obtain NICE approval was typically £30k per patient per year.  With Orphan drugs there is no such limit as QALYs and the other pharmacoeconomic tools are harder to relate to rare diseases.  Cerezyme is a good example of this.  Within England the cost per patient per year is ~£140k.  In the States orphan treatments are now approaching $1m per patient per year for gene therapy drug Glybera.

Prior to the relevant orphan drug legislation there was little incentives for pharmaceutical companies to invest into treatments for rare diseases.  The traditional search for the next ‘blockbuster’ drug helped to drive the pharmaceutical industry into hunting for larger and larger markets such as cardiology and infectious diseases.  The shift away from blockbuster treatments to more personalised therapies has enabled clinical trials to be performed more efficiently by reducing subject numbers and stratifying trial subjects to known responders.  Clinical trials for orphan drugs may include as few as 10-20 patients and this will often form part of the marketing authorisation application. 

An MA to match

As the number of clinical trial subject can be very low the EMA can issue a conditional or exceptional circumstance MA for orphan drugs.  A conditional MA is issued on the basis that a full dossier will be submitted in the future covering long term safety & efficacy data.  Once submitted and approved the conditional MA then reverts to the traditional MA model.  Exceptional circumstance Mas are issued when a full dossier is unlikely to be issued in the future due to the small patient numbers involved.  The MA therefore becomes conditional on the MA holder performing long term safety studies and an annual assessment by the COMP.  The legal basis for exceptional circumstance MA is EU regulation 726/2004 and the EMA website provides a good overview.  The exceptional circumstance MA can therefore allow pharmaceutical companies to get their novel product to market sooner and without the costs associated with large phase 2 and 3 clinical trials.  It must be noted that the three pillars of marketing authorisations (safety, quality & efficacy) still apply to both conditional and exceptional circumstance MAs.   

Summary

The rise in marketing applications for orphan drugs can be attributed to a number of factors such as legislative developments, business incentives and the advancement of new technologies within the pharmaceutical industry.  From a trainee QP’s perspective this post does not offer a great deal of information to help with your viva.  However, being aware of how the pharmaceutical industry is changing is important to show an awareness of the bigger picture.  

The exceptional circumstance and conditional marketing authorisations would provide an additional layer to your law and admin knowledge.