US FDA's Orphan Drug Designation Reviews Often Don't Include Regulatory Histories, GAO Says
Executive Summary
Lack of information may mean FDA cannot conduct a thorough review, but HHS argues that products usually are very early in development and therefore don't have a regulatory history to document.
Staff of the US FDA often did not record background information as required when reviewing orphan designation requests, the Government Accountability Office found, which GAO suggested called into question the extent of the agency's evaluations.
The findings may not be too dire however, as HHS argued the background information GAO said was missing is actually rarely available when a sponsor requests an orphan designation and may not directly affect the final decision.
Still, GAO said FDA must ensure that product sponsors' designation requests are accurate, which begins with "through and consistent evaluations."
"We found that FDA does not always ensure that all information is consistently recorded in its review templates and evaluated when making designation determinations, which are critical steps needed to understand the full context of a drug’s intended use in the rare disease," GAO wrote in a Nov. 30 report assessing the orphan designation process and rare disease drug development.
Drug sponsors also told GAO that orphan incentives are not a primary reason they develop drugs for rare diseases, and several stakeholders said high prices were a strong motivator to enter the space. (See sidebar.)
Orphan designation allows a sponsor to receive several incentives, including additional exclusivity upon the product's approval. FDA's Office of Orphan Products Development oversees the process.
GAO found many reviews did not include all the historical data required as part of the new template implemented in 2017, including US and foreign marketing history or previous orphan designations for both the drug and disease.
Of 148 designation requests reviewed, GAO said 102, about 69%, were missing one or more elements of the product's regulatory history and 19, about 13%, did not include all prior orphan designations for the drug and disease. (See chart.)
In one instance, the FDA reviewer failed to record any prior orphan designations for the disease that was subject to the pending request and then placed it in pending status over concerns about the manufacturer's accounting of whether the treatment population met the definition for orphan status. GAO said that disease, which was not identified in the report, had 36 related orphan designations at the time of the review, including seven that had been granted in 2017. The drug in question did receive a designation in May 2018, according to the report.
FDA reviewers also did not always include evidence from independent sources verifying the size of a patient population in 23 cases, about 16%.
GAO recommended FDA update internal guidance for instructing reviewers on how to use the information recorded in the review template, which could improve decision-making, as well as help secondary reviewers who ensure consistency and quality.
GAO reviewed designation applications submitted between October 2017, when FDA began using the new review template, and December 2017.
The review period came soon after FDA cleared a backlog of orphan designations that had been awaiting action, many for more than 120 days. Commissioner Scott Gottlieb ordered the backlog eliminated shortly after taking office in 2017, and he directed the office to return the goal for a completed review to 90 days. (Also see "FDA's Orphan Designation Backlog Plan Focuses On Efficiency, Not Staff" - Pink Sheet, 29 Jun, 2017.)
Resource constraints had forced OOPD to increase the goal to 120 days in 2016. (Also see "Orphan Designation Requests To Get Slower Reviews" - Pink Sheet, 10 May, 2016.)
Drugs Too Early To Have Regulatory History, HHS Says
HHS concurred with GAO's recommendations, but indicated there often was a reason some of the background information was missing.
Matthew Bassett, HHS assistant secretary for legislation, said in written comments included in the report that information in the background section of the template "may provide useful context for the reviewer," but "will not typically affect the outcome of the orphan-drug designation decision."
"Because orphan-drug designation occurs early in drug development, many drugs that are the subject of an orphan-drug designation request do not have relevant regulatory history background to document," he wrote.
Bassett also said that "it would be extremely rare for a drug at the designation stage to have had any adverse actions taken against it," pushing back against GAO noting reviewers' failure in some instances to document them.
GAO also said that in the cases where independent sources used to verify population sizes were not noted, the reviewers' experience with the disease may have made that step unnecessary. However, there was no documentation to confirm the determination.
FDA will consider the recommendations in its ongoing effort to train reviewers and evaluate and revise the pilot review template for orphan designations, according to the report. Bassett noted that the designation templates GAO reviewed were among the first to be completed since a pilot program launched.
OOPD Leadership, Services Changing
OOPD has undergone some leadership transitions in recent months and may have to prepare for an expansion of services going forward.
FDA appointed Janet Maynard acting OOPD director in late October, the fourth head of the office in the previous year. She took the position after Ilan Irony decided after about a month in the job to return to the Center for Biologics Evaluation and Research. (Also see "US FDA May Wait Until Late 2019 Before A Cures Hiring Enhancement Is Available" - Pink Sheet, 27 Sep, 2018.)
Deputy Director Debra Lewis ran the office in the interim, and had also served as head after Gayatri Rao left the position in December 2017.
FDA Principal Deputy Commissioner Rachel Sherman also said she envisions OOPD to eventually grow and function more like a consult office for rare disease drug development, a significant change from its current role. (Also see "US FDA Appoints Another Orphan Products Development Office Head Amid Growth Expectations" - Pink Sheet, 15 Oct, 2018.)