Analyst Report Suggests Recent Uptick in NDA/BLA Refuse-to-File Letters Signals Changes at FDA

April 26, 2011

By Kurt R. Karst –     

A recent report from Leerink Swann LLC analyst Howard Liang, Ph.D. suggests that what appears to be a recent increase in the number of Refuse-to-File (“RTF”) letters issued by FDA to NDA and BLA sponsors – some of which are large, experienced biotech companies – might signal both a greater willingness from FDA to issue such decisions, and therefore a higher filing threshold, and that filing decisions are no longer non-events.  

FDA’s regulations at 21 C.F.R. § 314.101 (drugs) and 21 C.F.R. § 601.2 (biologics) provide the bases for the Agency to RTF an application – generally because an application does not, on its face, contain information required under the FDC Act, under the PHS Act, or in FDA’s implementing regulations.  (Note that NDA/BLA deficiencies that serve as the basis for an RTF action are distinct from filing review issues, which pertain only to applications that have been filed.)  Over the years, FDA has issued guidance (here and here) on the Agency’s RTF policies, and has established a Clinical Hold/RTF Committee that since about 2008 is supposed to meet approximately 6 times a year. 

According to Dr. Liang’s analysis of 28 publicly known RTF actions since 1998 – 13 of which have been issued since 2009 and several of which have been issued to large, experienced companies – “[w]hile it is not possible to firmly conclude that the pace of RTFs has increased statistically due to a relatively small sample size and lack of disclosure of all RTFs, the fact that even the most experienced companies receive RTFs suggests a change at the FDA.”  (It is likely that FDA has, in fact, issued more than 28 RTF decisions since 1998, as FDA acknowledged in 2006 that although infrequent, about 5 RTFs had been issued per year.  RTF decisions are difficult to track as FDA does not disclose them; however, FDA has proposed as part of the Agency’s Transparency Initiative that “FDA should disclose the fact that the Agency has issued a refuse-to-file or complete response letter in response to an original NDA, BLA, or an efficacy supplement for an NDA or BLA at the time the refuse-to-file or complete response letter is issued, and should, at the same time, disclose the refuse-to-file or complete response letter, which contains the reasons for issuing the letter.”)  The breakdown of the types of issues that led FDA to issue the 28 RTF actions discussed in Dr. Liang’s analysis is provided below.

Source: Leerink Swann LLC “RTFs Suggest FDA Filing Decisions May Have Become More Meaningful Events,” April 25, 2011.  Reprinted with permission.

According to Dr. Liang, the apparent increase in RTF actions suggests a lower threshold for RTFs and “could be due to the agency's enforcement mentality under the new Commissioner.”  In addition, “the wave of RTFs may also be related to the recent FDA implementation of good review practices in an initiative called ‘21st Century Review’, says Dr. Liang.  “After a pilot program started in 2008, this process is being implemented to all BLAs and NDAs in FY2011,” says the analyst report.  According to FDA, the “21st Century Review Initiative,” which is based on the Agency’s Good Review Practices, “is a set of performance standards [CDER] follows when doing drug reviews that involve multiple offices” the goal of which “is to make the drug review process more organized and integrated, and ensure all decision makers are heard.” 

In addition to the issues identified by Dr. Liang in his report as contributing to more RTF actions, it is certainly possible that pressure put on FDA officials to meet PDUFA performance goals is causing some reviewers to more liberally use the RTF procedures to better manage the review queue.  It is also possible that the increase in RTF actions has been spurred by the apparent resurgence of FDA’s Clinical Hold/Refusal-to-File Committee, which is intended to, among other things, share divisional experiences as a means of teaching and learning.

Hat tip Pharmalot.