FDA Drowning in Orphan Drug Applications

Alicia Ault

October 19, 2016

CRYSTAL CITY, Virginia ― The various incentives meant to encourage the development of drugs for rare diseases have created an avalanche of products that the US Food and Drug Administration (FDA) is struggling to keep up with, said agency officials.

This comes in tandem with more, and ever more sophisticated, overtures to the agency from patient advocates who have rare diseases, who have been encouraged both by law and by the FDA to take a greater role in the development of products for their conditions.

It is a double-edged sword, said FDA officials at the National Organization for Rare Disorders (NORD) Breakthrough Summit held here. Orphan drugs are being approved at a record level, but the agency is not equipped to handle the rising tide of submissions, they said.

To be designated an orphan drug, a therapy must have a patient population of 200,000 or less, according to FDA rules.

Requests for orphan designation have doubled since 2010; in 2015, the agency received 466 requests, said Gayatri Rao, MD, JD, director of the FDA's Office of Orphan Products Development. "We are on pace to exceed this record number" in 2016, said Dr Rao.

It's a remarkable figure, considering that the FDA has approved just 575 orphan drugs since the Orphan Drug Act was signed into law in 1983.

Janet Woodcock, MD, director of the FDA's Center for Drug Evaluation and Research (CDER), told Medscape Medical News that the orphan program should not be viewed as a victim of its own success. "It isn't the rise in the number of development programs that's the problem," she said. "It's the fact that we can't recruit and retain adequate staff."

She said the agency had a legally imposed cap on hiring, and added that the FDA could not compete with pharmaceutical industry salaries.

Submissions Coming "Fast and Furious"

The applications for orphan designations "are coming fast and furious," said Dr Rao. Not all will make it through the FDA approval process, Dr Woodcock said. But, she added, recently, "orphans have a better track record getting approved" than drugs for diseases that are not rare.

In 2015, 21 of the 45 novel drugs (known as new molecular entities) that were approved by the FDA were orphan products.

For years, the Office of Orphan Products Development has issued initial decisions within 90 days, but that time frame is no longer possible, said Dr Rao. The reviewers now aim for 120 days and try to review at least 75% within that period. But, said Dr Rao, "from the most recent data, we are barely making that."

Mike Lanthier, a research analyst in the FDA's Office of the Commissioner, told the NORD Summit attendees that the number of submissions has "become a workload challenge."

But the agency still seems to be on target to pump out a bumper crop of orphan approvals in the coming year, said Noel Southall, PhD, an informatics specialist at the National Institutes of Health. He said he expected as many as 30 orphan approvals in 2017, many of which will be validations of completely new therapeutic technologies.

Among the products on deck: nusinersen for spinal muscular atrophy; voretigene neparvovec, a gene therapy for Leber's congenital amaurosis; and patisiran, an siRNA technology for amyloidosis.

Until recently, the majority of orphan drugs that received approval were for rare cancers, said FDA officials. Oncology continues to be a primary target, accounting for about a third of the orphan designations, said Dr Rao.

But neurology therapies are now in the second position, followed closely by gastroenterology products, she said.

Listening to Patients

The FDA showed up at the NORD Summit in force, with at least 25 agency officials in attendance or speaking, including FDA Commissioner Robert Califf, MD.

Dr Califf said that patients and their advocates were uniquely positioned to give valuable input to drug developers and the FDA and that their voice should not — and would not — be ignored at the agency. "I can assure you that the commitment to patient involvement in the system of product development and evaluation is deep and fundamental across the [FDA]," said Dr Califf.

The FDA was required under the reauthorization of the Prescription Drug User Fee Act (signed into law in 2012) to actively solicit patient input in the drug development process. As part of that, the agency has held 20 public meetings specifically seeking that input, and it will hold four more in the next year, said Pujita Vaidya, MPH, from the CDER's office of strategic programs. She urged NORD Summit attendees to come up with more topics for meetings.

But listening to patients does not mean giving science short shrift, said Richard Moscicki, MD, deputy center director for science operations at the FDA.

He said patients and advocates should seek rigorous data, in particular, natural history studies of diseases. They also should help develop assays and biomarkers that will help determine efficacy.

"You should demand good science," said Dr Moscicki.

Dr Califf agreed. "While speed to access is vital to suffering people, we also must continue to develop and implement methods to separate the wheat from the chaff," he said.

Follow Medscape on Facebook and Twitter .


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.