Does FDA Need Statutorily Imposed Incentives for Regulatory Compliance Matters?

April 17, 2018By Mark I. Schwartz

Last year, the President signed into law the Food and Drug Administration Reauthorization Act (FDARA) to revise and extend the user fee programs for drugs, medical devices and biosimilar biological products. Section 902 of FDARA requires FDA to publicly report, annually, information related to inspections of facilities necessary for approval of these medical products.

Not later than March 1 of each year, the Secretary of Health and Human Services shall post on the internet website of the Food and Drug Administration information related to inspections of facilities necessary for approval of a drug under section 505 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355), approval of a device under section 515 of such Act (21 U.S.C. 360e), or clearance of a device under section 510(k) of such Act (21 U.S.C. 360(k)) that were conducted during the previous calendar year. Such information shall include the following:

(1) The median time following a request from staff of the Food and Drug Administration reviewing an application or report to the beginning of the inspection, and the median time from the beginning of an inspection to the issuance of a report pursuant to section 704(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 374(b)).

(2) The median time from the issuance of a report pursuant to such section 704(b) to the sending of a warning letter, issuance of an import alert, or holding of a regulatory meeting for inspections for which the Secretary concluded that regulatory or enforcement action was indicated.

(3) The median time from the sending of a warning letter, issuance of an import alert, or holding of a regulatory meeting to resolution of the regulatory or enforcement action indicated for inspections for which the Secretary concluded that such action was indicated.

(4) The number of times that a facility was issued a report pursuant to such section 704(b) and approval of an application was delayed due to the issuance of a withhold recommendation.

Since this is the first report published under this statutory authority, we have nothing to compare it to. Nevertheless, the information is instructive. For example, in calendar year 2017, the median time between the issuance of a Form 483 for a cGMP inspection and the issuance of a Warning Letter was 191 days (or 6.4 months). For purposes of contrast, the agency’s own Regulatory Procedures Manual says that Warning Letters should be issued within four months of the appropriate reference date, which typically is the issuance of the Form 483:

To ensure the applicability of evidence to the present situation, the agency will strive to issue Warning Letters within four months from the appropriate reference date. Examples of the appropriate reference date are: the last day of the inspection, the date of sample analysis, or the date of evidence collection.

So, to summarize, in 2017, the median issuance time for an agency Warning Letter was 2.4 months longer (or 60% longer) than the goal set out in the agency’s own procedures. It is also well established that, not infrequently, the agency issues Warning Letters up to a year or more from the date of issuance of the Form 483. Clearly, there is room for significant improvement in the speed with which the agency issues Warning Letters.

In calendar year 2017, the median time between the issuance of a Form 483 and the occurrence of a Regulatory Meeting was 169 days (or 5.6 months). A Regulatory Meeting is a meeting requested by FDA management to inform responsible individuals or firms regarding how one or more products, practices, processes, or other activities are considered to be in violation of the law.

The Regulatory Procedures Manual does not provide timelines for the convening of a Regulatory Meeting. Nevertheless, the notion that a firm would need to wait, on average, close to half a year to discuss their Form 483 observations (or their responses to the Form 483) with agency regulators seems unduly limiting, particularly in situations where the Form 483 could be used as a basis to prevent the importation of the firm’s products (i.e., an import alert) or to prevent approval of a pending application (i.e., a compliance check).

In calendar year 2017, there were no resolutions for compliance actions for facilities that were issued a Form 483 in CY 2017, and that had resulted in a Warning Letter, Import Alert, or a Regulatory Meeting, and were named in a pending application.

As the agency states in this report, given the significant remediation efforts and re-inspection by FDA that would be required for resolution, it is unlikely that a site would be inspected, regulatory action taken, and resolution completed within a single calendar year. Perhaps that is part of the problem that Congress was attempting to point out or, more likely, Congress had no idea that it was entirely unrealistic that FDA, as it is currently run, would be able to resolve the compliance action in the same year in which the compliance action was initiated.

In addition, in calendar year 2017, 94 applications were denied approval solely due to a facility-related withhold recommendation because of the lack of compliance at a facility discovered during an inspection that had been completed in that calendar year.  (Biological products reviewed under section 351 of the Public Health Service Act were not included in this report.)  Also, in 2017, the median time between an inspection request from FDA staff to the beginning of an inspection was 102 days, and the median time between the beginning of a prior approval inspection and the issuance of a Form 483 was seven days.

In summary, it will be interesting to track how these timeframes change in the coming years. However, without the introduction of statutorily mandated incentives, such as currently exist under FDARA for review times of NDAs and BLAs, it is doubtful that we will see significant improvements in the issuance time of agency Warning Letters and in the convening of Regulatory Meetings.

This is all to the detriment of industry and the agency alike. After all, the longer it takes FDA to issue a Warning Letter or convene a Regulatory Meeting with non-compliant firms, the longer it will take the firms in question to resolve the issues at hand, bring the facilities back into cGMP compliance and, where relevant, bring the drug products back into distribution.