Orphan drug development takes 15.1 years to go from first patent filing to product launch, 18 percent longer than the average time required for all new drugs, according to the Tufts Center for the Study of Drug Development. And development time for drugs to treat ultra-orphan diseases—which affect only a few hundred patients in the U.S.—is even longer: 17.2 years.
The numbers are startling because they were measured differently, said Christopher-Paul Milne, research associate professor and director of research at Tufts CSDD who conducted the analysis, looking at 46 first-in-class orphan new molecular entities approved by the FDA between 1999 and 2012.
Others who have scrutinized orphan drug development timelines have focused on the period after new drug application (IND) to time to FDA approval. That, contends Milne, hasn’t provided the most accurate picture.
Tufts measured development time from first patent filing. Developers of orphan drugs “have a lot of problems before even getting the IND, like having to identify every patient who has the disease,” said Milne. “You have to understand a lot about the disease when you’re looking at first-in-class new molecular entities. These are the newest of the new.”
Other key findings from the report:
- From 1983 through 2017, nearly 4,000 drugs have received orphan drug designations in the U.S., and more than 650 have been approved for marketing.
- In 2016, the FDA granted 333 (57%) of 582 orphan drug designation requests it received, or 10 times the number of designations granted in 1986 shortly after inception of the Orphan Drug Act (ODA).
- The number of approvals as a share of designations declined during the last few decades, to 12% in 2016, slightly lower than the 17% share for the entire 1986-2016 period.
While the number of orphan designations has grown dramatically over the past two decades, said the report, growth in the number of orphan approvals during the same years has been more modest.
Approvals as a share of designations for oncology orphan drugs outpaced all other therapeutic areas. Said the report, the emphasis on oncology orphan drug development reflects, in part, an increased understanding of biological pathways of cancer, as well as a favorable reimbursement environment.
But challenges to this burgeoning new area of drug development were numerous. They included variability in expression, severity, and/or course of the disease; geographically dispersed population; small population; selecting among multiple pathways; lack of endpoints and outcome measures; required flexibility in regulatory decision making; biology of disease not understood; natural history of disease not well known; and translating new knowledge into useful knowledge.
One-third of the developers responsible for the 46 first-in-class orphan NMEs approved during 1999-2012 said they encountered four of these challenges, 15 percent of them faced six challenges, and 11 percent faced two. None reported facing fewer than two.
“We were surprised that there are so many special challenges,” said Milne. “For instance, sometimes a disease was very different in men versus women. Sometimes it was very different in a child versus an adult. That explains why the FDA put a grant program for studying the natural histories of diseases in the latest version of 21st Century Cures Act.”
While Tufts measured the development of orphan drugs from first patent filing to product launch, others say the most accurate way to measure development timelines in orphan drugs is still an unsettled area.
“There are differing opinions on what qualifies as the start of drug development,” said Anne Pariser, director of the Office of Rare Diseases Research within the National Institutes of Health’s National Center for Advancing Translational Sciences (NCATS). “Some people consider using clinical development time, defined as investigational new drug application filing.”
Others, like Tufts, start before that, she said, and get a far different measurement, which can lead to greater confusion.
And Bernard Munos, senior fellow at FasterCures, founder of InnoThink Center for Research in Biomedical Innovation and a former corporate strategy adviser at Eli Lilly, said Tufts’ focus on new molecular entities to the exclusion of other types of orphan drugs presented an incomplete picture.
Munos pointed out that the orphan drug universe is comprised of two subsets: new molecular entities, for which developers face the challenge of small patient populations; and the re-purposing of drugs already approved for non-orphan indications. The second subset, said Munoz, does not follow the same economics as the first.
He points out that an analysis by Kaiser Health News and National Public Radio last year found that one-third of orphan drugs approved since the program began in 1983 were either repurposed mass market drugs or drugs that received multiple orphan approvals. (The link to this analysis is found below.) The analysis showed this repurposing has been increasingly used in recent times to “evergreen” patents on major drugs.
Pariser also took issue with the fact that Tufts only included orphan drugs developed through 2012 in their study.
“It’s important to consider some of the very positive changes that have occurred in the orphan drug field since then,” said Pariser.
For example, she said, in 2012, the FDA’s Breakthrough Therapy Designation was implemented, granting priority review to drug candidates if preliminary clinical trials indicate that the therapy may offer substantial treatment advantages over existing options for patients with serious or life-threatening diseases. The majority of those have involved rare/orphan drugs, some of which have had very short timelines for development—in some cases, as quick as two and a half years, she said.
“Another important point to consider is the use of biologics, which was not included here,” said Pariser, explaining that many orphan drugs increasingly are biologics and the development time for biologics tends to be shorter than for drugs.
Said Milne, Tufts’ research helped to show that new approaches to study design—including use of patient advocacy groups and adaptive clinical trials—are helping to mitigate development problems.
