GAO Raises Questions on FDA’s Orphan Drug Designation Process

Regulatory NewsRegulatory News | 30 November 2018 |  By 

The Government Accountability Office (GAO) announced Friday that it has found that the US Food and Drug Administration (FDA) does not always ensure that all information is consistently recorded and evaluated when making orphan drug designation determinations.

The missing of these critical steps by the agency in some cases means that FDA reviewers do not fully understand the context of a drug’s intended use for the rare disease, GAO said.

“The Commissioner of FDA should ensure that information from orphan drug designation applications is consistently recorded in OOPD [Office of Orphan Products Development] review templates and evaluated by OOPD reviewers when making an orphan designation decision,” GAO recommended.

The recommendation follows an inquiry from Sens. Orrin Hatch (R-UT), Chuck Grassley (R-IA) and Tom Cotton (R-AR) on potential abuses of the Orphan Drug Act. Grassley also has said he is looking into abuses of the act that allow such incentives, meant to encourage drug development for rare diseases, to be bestowed on a drug that actually reaches a larger population than what it won the orphan designation for, or companies that conduct limited research to win approval for such a drug.

However, the GAO report did not address such abuses and delved more into the processes by which FDA evaluates orphan designation requests.


FDA generally evaluates orphan designation requests by looking at the size of the rare disease population and the company’s scientific rationale that the drug may effectively treat the disease. To inform their evaluation, reviewers must record certain background information in a standard review template, such as the drug’s marketing history. Officials told GAO that this information provides important context, such as whether FDA has experience with a rare disease, which is critical to ensuring a complete designation application review.

However, GAO’s analysis of 148 designation review templates found that FDA does not consistently record or evaluate background information when making designation decisions. “For example, 48 of 148 review templates GAO analyzed were missing information on the drug’s US marketing history. As such, FDA cannot be sure that reviewers are conducting complete evaluations that include all critical information needed for assessing its criteria,” GAO said.

In addition, GAO found that despite requiring reviewers to record background information for each orphan designation application, OOPD’s guidance does not provide instructions on how to use this information when evaluating the applications.

OOPD instructs its reviewers to consider evidence found in independent sources to verify the population estimate provided in a designation application. However, in 23 of 148 OOPD review templates, reviewers did not include the results of any such independent verification in their evaluation of the manufacturer’s population estimate.

In response to the recommendations, the US Department of Health and Human Services (HHS) said the recommendation would be considered as part of FDA’s ongoing efforts to evaluate and revise the designation review template and to train reviewers.

“Regarding the background information in the review template, HHS also noted that many drugs requesting orphan designation do not have relevant regulatory history, particularly adverse actions, as these drugs are early in drug development at the time of requesting orphan designation. However, HHS agreed with the importance of consistently documenting and utilizing background information, and stated that FDA will continue to apply consistent criteria to its review decisions,” the GAO report said.

GAO further said that FDA has a number of options to ensure that its reviewers obtain all necessary information and use it to inform orphan designation determinations.

“For example, we found that FDA’s guidance was not always clear in instructing reviewers how they should use the information they record. Clarifying these requirements in guidance could help reviewers make use of this information, including the secondary reviewers who ensure the consistency and quality of designation reviews,” GAO said.


A drug is eligible for orphan designation when it is intended to treat a disease that affects fewer than 200,000 people in the US. Manufacturers receive incentives, including tax credits and exclusive marketing rights, for developing drugs to treat rare diseases.

According to OOPD data, the number of new designation applications received by FDA grew from 185 in 2008 to 527 in 2017 – an increase of 185%.

“According to FDA, the growth in orphan designations and marketing approvals is expected to continue, partly due to medical advances that make health care more personalized, genetically targeted, and likely to address rare diseases,” the report says.

In addition, OOPD data on the 3,690 orphan designation applications received from 2008 to 2017 revealed that the majority met the necessary criteria and were granted orphan status. Specifically, about 71% of applications were granted orphan designation as of April 2018, while the other designation applications were placed in a pending status awaiting a manufacturer’s response to OOPD concerns (21%), denied orphan designation (5%) or withdrawn (2%).

The most common reason OOPD did not grant orphan designation was concerns with the adequacy of the manufacturer’s scientific rationale, GAO found.

“OOPD reviewers noted various concerns with the scientific rationale provided in these designation applications, including that the manufacturer did not provide sufficient or adequate data to support their scientific rationale, or that the manufacturer did not provide data from the strongest available model for testing the drug,” the GAO report says.

GAO Full Report


© 2022 Regulatory Affairs Professionals Society.

Tags: GAO, OOPD, orphan drug

Discover more of what matters to you

No taxonomy