Several entities within the medical device industry are calling attention to a provision within a recent draft guidance published by the US Food and Drug Administration (FDA) that they say offers little in the way of clarification and could potentially be a sticking point during complicated and contested review proceedings.

Background

In March 2013, FDA released a long-awaited guidance entitled Types of Communication During the Review of Medical Device Submissions. The guidance is supposed to reflect changes called for under two recent pieces of user fee legislation, the FDA Safety and Innovation Act of 2012 and the Food and Drug Administration Amendments Act of 2007.

Specifically, both pieces of legislation called for increased communication between sponsors of medical device applications and regulators in the hopes of resolving issues earlier in the review cycle and without as much back-and-forth, allowing for a faster and smoother review of a medical device. These "communication commitments," as FDA calls them, generally fall into four categories: acceptance reviews, substantive interactions, interactive reviews and MDUFA date meetings.

More information on the guidance may be found here.

Additional Information (AI) Letters

While much of the guidance won cautious praise from members of industry who weighed in on the guidance, one provision seemed to catch negative attention from most entities: Additional Information (AI) letters.

AI letters are used by FDA to request information from a sponsor regarding an aspect of their application, particularly during an interactive review process in which regulators and industry are working more closely through information interactions. For example, if FDA finds an error that falls short of a "Major Deficiency" (but more than a "minor" deficiency) it may send a sponsor an AI letter in an attempt to compel it to fix the error.

This is not to say that FDA is always correct in its assertions. The sponsor may acquiesce to the letter and make changes, but sponsors may also respond to the AI and argue against whatever changes are called for. FDA may reject this response, leading to an impasse that would likely derail the application if no changes are made.

FDA's guidance goes on to note that, "In limited circumstance, a second AI letter for a 510(k) may be appropriate" in cases where there are outstanding deficiencies following an applicant's response.

"One example of such a circumstance would be when a first AI letter indicates that FDA believes no predicate device exists, but the submitter is able to identify a predicate," FDA explained. "A subsequent review of the comparison of the subject device to the newly identified predicate could raise questions appropriate for a second AI request.  Other instances in which a second AI request could be issued should be limited and occur only with concurrence of Division-level management."

In addition, FDA notes that second AI letters may sometimes be requested by a company in order to place the submission on hold to permit it to complete performance testing to address noted and outstanding deficiencies in an application, but that such uses are inappropriate and "contrary to the stated goal" of its user fee programs.

Industry Comments

Though FDA's explanation of the section was short, it led to a lengthy response from medical device manufacturer Cook Medical, which said it was "discouraged … by comments about a second AI letter."

The problem, Cook wrote, lies with the options available to FDA during the interactive review process. "In many situations, FDA's first AI letter will state that the manufacturer needs to conduct a very specific test or justify why no test is necessary," Cook noted. As stated earlier, many companies attempt to do the latter and justify why that testing is not necessary. If FDA rejects this, the sponsor would be required to conduct the testing, which Cook notes would exceed the amount of time allocated for a response under the interactive review process.

"Rather than issuing a 'Not Substantially Equivalent' (NSE) letter, it is only reasonable to issue a second AI letter," Cook explained.  "The guidance should acknowledge that, when FDA rejects an alternate test or justification given in response to the first AI letter, a second AI letter should be issued."

Industry group AdvaMed, too, flagged the section, explaining that "additional AI letters may be appropriate when FDA requests additional data following review of a Substantive Interaction Response."

"It is important to note that not all data requirements may be evident in a Pre-Submission meeting, and/or that FDA has become aware of a concern/new information that prompted its request for additional data once a submission is under review," it added.

The Orthopedic Surgical Manufacturers Association (OSMA) also flagged the section, recommending that it be removed in its entirety.

"If extension past the goal is required based on new questions raised by the AI #1 response and that extension is consented by the applicant, this should remain an option; more resources are spent on both sides starting a submission from scratch," it explained.

FDA Docket

FDA Guidance