Orphan Drug is Generally Not the First Step to Non-Orphan Approval  

About two-thirds of drugs approved as orphan drugs in the last 20 years did not get subsequent approval for other indications, and only 6 orphan drugs out of the 451 approved by FDA ended being top-selling drugs. Conventional wisdom in the industry has been that orphan designation could be the proverbial foot-in-the-door to get subsequent approval for non-orphan indications via NDA supplements, but data presented by FDA at this week’s Rare Diseases Summit shows that only 7% of the drugs originally approved as orphan drugs were later able to get approval for non-orphan indications. Although surprising, there could be several reasons for that. Orphan drugs are given special treatment by FDA during review of the clinical development plans, manufacturing reviews and data presented in support of the market approval application. The review is prioritized in most cases, and FDA provides multiple incentives to develop products for orphan diseases such as requiring fewer clinical and non-clinical studies, support with clinical protocol development, and faster meetings and responses. The regulatory conditions could be even more favorable for rare diseases, those that affect far below the 200,000 threshold for the orphan indication. However, when the same drug is pursued for non-orphan indications, all those incentives disappear and the sponsor has to do all the conventional development steps that they did not do for the previous orphan indication. The sponsors of the orphan application, it seems, are not prepared for the conventional development pathway as shown by the low rate of conversion from orphan to non-orphan indications. Another reason could be that orphan indications potentially have a significant return on investment (ROI) due to the niche markets and monopolies making it less attractive to pursue non-orphan highly competitive and expensive non-orphan indications that may not promise similar ROI. It is ironic that the attractive regulatory models for orphan drug development could in turn be responsible for these drugs not being developed for other non-orphan indications. It is obviously an over-simplification of the conditions and likely there are orphan drugs that are also being developed for non-orphan indications but the available data shows that there is little overlap between orphan and non-orphan drugs.