Federal investigation finds holes in orphan drug approval process

The U.S. Food and Drug Administration's process for reviewing drugs that aim to treat rare diseases lacks thorough documentation that could prevent a life-saving antidote from getting to market, according to a new report.

Regulators are looking for two main criteria in their orphan drug application reviews—the size of the rare disease population and the scientific rationale that the drug may effectively treat the disease. Once the product earns the designation, the drug manufacturer can then apply for marketing rights.

But in the U.S. Government Accountability Office's review of 148 orphan drug applications submitted in late 2017, investigators found that about 69% (102) were missing one or more elements of the regulatory history of the drug. Regulatory histories include marketing in both the U.S. and abroad, active investigational new-drug applications, and adverse actions.

Nearly 13% didn't capture all prior orphan designations for the drug and disease. In one case, a reviewer placed an application in pending status due to concerns with the manufacturer's population estimate. But the reviewer missed prior orphan designations for the disease that had 36 related orphan designations at the time of the review, seven of which had been granted in 2017.

"As orphan drug designations and approvals continue to rise, we have less certainty that newly approved orphan drugs were adequately vetted for the orphan designation prior to approval," said Dr. Michael Sinha, a research fellow at the Harvard-MIT Center for Regulatory Science at Harvard Medical School.

FDA officials said that this type of background information is vital when an application is for a drug treating a disease with little published information available. They can look to other FDA divisions that may have experience with the disease. Additionally, the prior orphan designation history can help the reviewer identify previously accepted methodologies to estimate the population for a disease.

The GAO found that 16% of the applications did not include the results of independent verifications of the population estimates. Of the 148 applications the GAO analyzed, reviewers granted orphan designations to 26 missing required information.

The FDA agreed with GAO's recommendation that the information from the orphan drug designation applications should be consistently recorded in the background section of its pilot review template.

"While we've had a record number of approvals for rare disease products recently, there are still no treatments for the vast proportion of rare diseases or conditions. The FDA is committed to doing what we can to stimulate the development of more products by improving the consistency and efficiency of our reviews, streamlining our processes and supporting rare disease research," the FDA said in a statement. Currently, only about 5% of rare diseases have treatments approved, the agency noted.

The FDA has tried to speed up the orphan drug review process. In June 2017, the agency's modernization plan aimed to eliminate the backlog of some 138 applications within 90 days as well as review new designation applications within 90 days of receipt.

To achieve those goals, the agency tasked senior reviewers to focus solely on the backlog of designation applications, clearing the backlog in about two months. The FDA also submitted a new review template that reinforced the proper check list, which helped streamline the review process.

This plan was set in place as orphan drug designation applications grew, increasing from 185 submitted in 2008 to 527 in 2017.

Although there might be holes in the documentation process, that doesn't mean that FDA reviewers aren't weighing the impact of a drug's regulatory or marketing history, said David Rosen, a partner with Foley & Lardner.

"The fact that maybe all the i's aren't dotted or t's aren't crossed is a technical claim, but whether it has a true material bearing is another story," said Rosen, adding that the FDA has many experienced reviewers.

The Orphan Drug Act was enacted in 1983 to provide drug manufacturers with incentives for developing treatments for small patient populations that were not expected to be profitable. Those incentives include seven-year exclusive marketing rights and a 50% tax credit for clinical testing costs.

A recent Health Affairs study notes that the seven-year exclusivity has an increasingly limited impact, Sinha said. The incentive did little to protect returns on investment in research and development for rare disease treatments and was often eclipsed by available patent terms for new drugs, researchers found.

From 2008 to 2017, 53% of orphan drug marketing approvals were in one of two therapeutic areas that were also common for granted designations: oncology (42.5%) and hematology (10.8%), according to the report. There were 27 different therapeutic areas overall, with seven of those areas having 10 or more approved orphan drugs.

"However, other incentives make orphan drugs particularly lucrative to manufacturers and costly to the healthcare system—for instance, smaller pivotal trials, high prices and decreased likelihood of generic competition upon expiration of market exclusivity," Sinha said.

A drug can earn orphan status even when it treats a non-rare disease, as long as a property of the drug (toxicity profile, mechanism of action or prior clinical experience) limits its use to a population of less than 200,000. This opens a loophole for drug manufacturers to game the system, some critics contend.

The majority (62%) of orphan drug marketing approvals from 2008 to 2017 have been for a new drug not previously approved for any use, the report found. The remainder have been for a new indication for a drug previously approved to treat a rare or non-rare disease.

GAO researchers also talked with industry experts and patient advocacy groups to identify other barriers in getting drugs for rare diseases to market. Stakeholders expressed a need for more basic scientific research, including understanding patient experiences and progression of symptoms. They also said it's hard to recruit enough people for clinical trials.

"We need to stimulate development and continue to support the orphan drug process," Rosen said.