Getting an orphan designation isn't as simple as just targeting a rare disease. Tim Coté, former director of the FDA's Office of Orphan Products, tackles the most common mistakes companies make

"The three most important things for companies tackling rare diseases to get right are regulatory affairs, regulatory affairs, and regulatory affairs," says Tim Coté, former director of the FDA's Office of Orphan Products and signatory to decision letters for over 1,400 orphan designation applications. 

"Get your regulatory affairs straight and everything will be well. "People think that doing great science is all that really matters, but the value of that science doesn't crystallise until you receive an affirmative regulatory affairs action. The major problem people have is that they're so busy doing the science that they totally forget about that until it's late in the game." 

Orphan designation is an early regulatory pathway companies can apply for in both the EMA and the FDA, providing financial and market-exclusivity incentives for rare-disease drugs that meet certain criteria. 

But Coté says that companies make many mistakes when applying for an orphan designation. 

"It's complicated because people have less experience with it, and many people don't really understand that orphans are different. They have to learn new processes while unlearning a lot of what they used to think about how a drug gets approved. The statute says that in order to be approved for marketing you have to show substantial evidence of both safety and effectiveness, and there's no numbers in that. About six months ago the FDA approved a product based on a pivotal trial of four patients. There were no p-values there, but there was substantial evidence of safety and effectiveness, and it was for a population of only around 20 patients worldwide who have this disease." 

He adds: "The dancing of molecules is somewhat irrelevant to the regulator; they want you to demonstrate that you can make the sick well, which is a lot different from measuring a decrease in a particular metabolite. 

"The upshot of that is that they are incredibly flexible with regards to orphan drugs, but they won't approve products just based upon hope, or just because it's rare." 

Coté now runs a consultancy, Coté Orphan, to inform people about the orphan drug process and help them to avoid making errors. 

"There are a lot unwritten rules surrounding orphan designation, and it's very difficult to know those rules unless you've actually worked there. For example, many people make mistakes about subsetting – they think diseases can be subset a certain way when they can't or they overlook opportunities for subsetting that may be completely acceptable but they don't understand yet." 

The most common mistake people make, though, is believing that a drug is obviously an orphan product before it's even got Orphan designation. 

"Often investors will take it at face value that something is an orphan because a client says it is, but that's not necessarily the case until you actually get the designation," says Coté. "For example if the disease you're targeting is considered a subset of a common disease, you need to demonstrate that it doesn't work outside of that subset, which is not usually the case.

"This is important because often the entire business model rests on the ability to secure orphan designation; if you think you're going to get exclusivity it's a totally different business proposition than if you don't have that exclusivity." 

But it is easy enough to find out early on if a product is worthy of an orphan designation: "Orphan designation can be done without any clinical data," says Coté. "People don't even know that sometimes. Talk to the agency early and often. If you're tardy to the party on orphan designation, then you're going to miss out on tax credits which are going to be important for whoever acquires your asset." 

Coté adds that while most of the challenges companies face in getting orphan designation are the same between the FDA and the EMA, there is a lot the two agencies could learn from each other. 

"In the US it's very simple – you write an application then you stick it in the mail. But in Europe your first step is deciding what your submission date is and requesting a submission date at least two months prior to the actual date itself, and then you have to have a pre-submission meeting as well. 

"On the other hand, one thing the FDA could learn from the EMA is that the criteria for orphan diseases is much better in Europe. In Europe a prevalence of five patients or less out of every 10,000 people is the definition for an orphan disease. In the US it's a static number, 200,000, but since we passed the law our population has increased 50 percent, meaning the criteria for rarity has got smaller and smaller."

Coté reiterates that for most companies the best thing to do is get help in navigating these complexities. 

"Don't feed yourself to the tigers without some assistance. If it's not me then ask somebody who knows orphan drugs inside out. I see too many people going in blindly and really not understanding the framework through which their stuff will be seen. You need to see it through the regulator's eyes and people tend not to, they see it through their own eyes." 

Orphan designation criteria & benefits

EMA 

To qualify for orphan designation, a medicine must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating. The prevalence of the condition in the EU must not be more than five in 10,000, or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development. No satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorised, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition. 

Sponsors who obtain orphan designation benefit from protocol assistance, a type of scientific advice specific for designated orphan medicines, and market exclusivity once the medicine is on the market. Fee reductions are also available depending on the status of the sponsor and the type of service required.

FDA 

The disease or condition for which the drug is intended must affect fewer than 200,000 people in the United States. 

Companies must also demonstrate that there is 'promise' that the drug will be effective in treating the disease, usually through clinical data, and that it is clinical superior to other similar drugs that have received orphan designation for the indication. 

Drugs with orphan designation are eligible for grants, 50 percent tax credit for expenditures incurred during the clinical testing phase, and a seven-year marketing exclusivity period.