Engaged for 20 years: an orphan drug designation from 1995 just got approved in 2018

The Food and Drug Administration (FDA) set a new record in 2018 with the highest number of new drug approvals in the last two decades.

With 59 new molecular entities approved, 2018 represents a big departure from a disappointing 2016 when the FDA approved only 22 new drugs, the lowest number since 2010. 

The FDA also set a new record in orphan drug approvals in 2018, granting 86 new marketing authorizations for drugs treating rare diseases. 

This number is higher than the total number of “new drug approvals” because not all of these drugs are new to science. Some of the drugs being approved for a rare disease had been previously approved for treating other diseases, so they count as an orphan approval but not as a “new drug” approval. Other drugs, such as Epidiolex (cannabidiol), are indeed new drugs, but because they are being approved to treat two orphan indications, in this case Dravet syndrome and Lennox-Gastaut syndrome, they count as two in the list of orphan drug approvals.



An interesting observation is that despite having more approvals of orphan drugs in 2018 than in prior years, the number of orphan drug designations for 2018 was much lower than in the previous year, with 335 designations in 2018 versus 477 a year before.

This happens because orphan drug designations are granted to drugs that intent to treat a rare disease while they are still at some point during development, prior to marketing authorisation. Some drug sponsors might request and obtain the orphan drug status (designation) many years before their drug is approved, potentially at a preclinical stage as soon as they have compelling data in animal models to support a possible benefit for patients with that rare disease. This happens in approximately one third of the orphan drug designations that are granted. In other cases, the drug sponsor might seek the designation after obtaining clinical data, usually in a Phase 2 clinical study, so for that particular drug the time between obtaining the orphan drug designation and the marketing authorisation might be much shorter.

Essentially, the orphan drug designation is like an engagement ring that the regulators grant to a drug in development for rare diseases.

And just like with engagements, it is expected that some time after that ring will come a marriage, although this is not always the case. Indeed, not all drugs that obtain an orphan drug designation during their development end up successfully reaching the market, and only a fraction of all orphan designated drugs become actual approved drugs that reach the patients.

This is very important, because within the patient community there is the expectation that most if not all of the drugs that obtain an orphan drug designation for their disease will eventually reach them. And more importantly, it is tempting, and common, to believe that once a drug obtains the orphan designation, it will not take much longer before it gets approved.

But what does “not much longer” mean in this case? 

I have used the data that the FDA has released about all of their orphan drug approvals for 2018 to analyse this very important question:the delay between orphan drug designation and orphan drug approval.



The FDA granted 86 marketing authorizations in 2018 for drugs treating rare diseases. The FDA also makes the date of the orphan drug designation for each of these drugs available, so it is possible to track the time that it took them to get from designated to approved – and the numbers are not pretty.

Orphan drug designations 2018.png

 What you see in the figure is all of the 86 orphan drug marketing authorisations from 2018 ranked by the number of years that it took them to get from designation to eventual approval in 2018. Again: those are years, not months.

In sixteen of these approvals, the drug had been designated as an orphan drug for treating that rare disease 10 or more years before it was eventually approved. In two cases it took 20 or more years.

Many of the approvals were for drugs that had received the orphan drug designation4 to 8 years before marketing authorisation.

The distribution is so broad that it means we cannot use the number of orphan drug designations for a disease, or the date of the designations, as an estimate of when that disease will see a drug approved. It might end up with 3 drugs approved in 3 years, or waiting 20 years to get the first drug approved. Every drug approved in a single year has a very different story of how it got there, and how look it took it.



To understand a bit better what leads to such a large difference in times from orphan drug designation to drug approval, we can look at the story behind the 5 approvals for drugs treating epilepsy syndromes. These are the ones highlighted in yellow in the graph.  

The two drugs that tool more than 9 years to progress from orphan drug designation to approval are everolimus and stiripentol. 

  • I have written about everolimus before. Everolimus (Afinitor, by Novartis) is similar to rapamycin, and had been already approved for multiple indications in transplantation medicine as well as for treating Tuberous Sclerosis Complex (TSC), a rare genetic disease. Everolimus obtained the orphan drug designation for treating TSC in 2009, and was first approved under that designation for treating a type of tumor characteristic of TSC in 2010. After seeing that the treatment also had efficacy in treating seizures in these patients, Novartis run additional trials focused on this disease aspect and this is how everolimus obtained the marketing authorization as an orphan drug for treating epilepsy in patients with TSC in 2018, nine years after the initial orphan drug designation.


  • The story of stiripentol is quite different. Stiripentol (Diacomit, by Biocodex) had completed two clinical trials for treating Dravet syndrome and obtained orphan drug designations for treating this rare disease by the EMA and FDA in 2007 and 2008 respectively. The European agency granted stiripentol a conditional approval in 2007, which was later confirmed as regular marketing authorization, but the FDA did not approve the drug. For the next 10 years, stiripentol was in the market in Europe and Dravet syndrome patients in the US had difficulties to access it and have it reimbursed as a non-FDA approved drug. Then in 2018, after the 10-year European orphan market exclusivity had ended for stiripentol, the FDA finally approved it. In a way, this approval represents a regularization of the drug in the US market, while it had been already approved for that same indication in Europe for over a decade


  • The two lines at the center of the graph with about 4 and half years of delay between orphan drug designation and marketing authorization are the two approvals of cannabidiol oral solution (Epidiolex, by Greenwich Biosciences)for Dravet syndrome and for Lennox-Gastaut syndrome, two rare epilepsy syndromes. The drug obtained the orphan drug designation of these syndromes in late 2013 and early 2014 respectively on the basis of early clinical data, and after completing two pivotal trials for each of these indications it obtained both marketing authorizations in 2018. The story of Epidiolex would be the usual one for a new drug that obtains the designation early in the development processand after 3-5 years completes its clinical development program and gets approved. 

  • At the very right of the graph there is a drug with very short period between orphan drug designation and approval, less than 2 and a half years, which is more often the story of older molecules that get re-developed for an orphan indication. In this case the molecule is midazolam, a widely-used benzodiazepine. In February of 2016, Meridian Medical Technologies obtained the orphan drug designation for the use of midazolam (Seizalam) for treating status epilepticus in adults. The new product is a reformulation of an old molecule for an indication where it was already used, and the company obtained marketing authorization for the intramuscular delivery of the molecule. Because in this case a complete development program was not necessary, and because the orphan drug designation came rather late in the development process, the story of Sezalam is an usual one


If you are still wondering about the drug that took 23 years between receiving an orphan drug designation and reaching the market, it is pegvaliase-pqpz (Palynziq, from BioMarin) for the treatment of Phenylketonuria (PKU). Palynziq is a recombinant protein and was granted the orphan drug designation for treating PKU in 1995. In the press release after approval, BioMarin’s CEO Jean-Jacques Bienaimé, highlighted how this approval represented “the culmination of more than a decade of perseverance by BioMarin employees”. An engagement with the FDA of over 20 years is indeed, a story of perseverance.


Ana Mingorance, PhD