When a Warning Fails

How FDA is Changing its Approach to Regulatory Compliance Oversight

When a warning fails

A warning letter from the Food and Drug Administration (FDA) has historically carried an ominous fix-it-or-else message to manufacturers of regulated products. According to FDA’s Regulatory Procedure Manual, warning letters - in addition to being the agency’s primary means to achieve prompt voluntary compliance - remain a primary means to establish prior notice. A prior notice helps the agency strengthen its position in enforcement actions by establishing that responsible individuals continued to violate the law despite having been warned by the agency.

In short, a warning letter is the agency’s way of giving you a final chance. Behave, or you will face painful enforcement actions such as a recall, seizure, civil money penalties, or worse still, jail time for responsible individuals. It carries a big stick, and predictably, manufacturers have been quite fearful of receiving a warning letter.

One of the unintended consequences of this practice has been a strong focus on Compliance, rather than fixing underlying issues within the Quality Management System (QMS). The QMS has become synonymous with a proliferation of burdensome procedures and documentation requirements. A lot of effort goes on in checking and re-checking documents instead of focusing on practices that inherently drive non-compliance in the first place.

Our analysis of the medical device QMS related warning letters issued in 2018 and early 2019 shows the top areas of violations continue to be Design Control, Corrective and Preventive Actions (CAPA), Complaints Handling, Medical Device Reporting (MDR), Production and Process Controls (P&PC). Some of the key themes in these areas point to basic deficiencies in the QMS:

  • Procedures incomplete, inadequate or not established

  • Deficiencies in design validations – testing, acceptance criteria, risk analysis

  • Verification and approval of design changes not documented; design transfer completed without process qualification

  • CAPA activities not documented, required data sources not analyzed, effectiveness checks not performed; adverse impact assessments not done

  • Complaints not documented, complaint evaluation and investigation not done; late MDRs

  • Process validation inadequate or not performed

  • Deficiencies in environmental controls, contamination controls

  • Management responsibilities, internal auditing, personnel and training

These top areas and themes have not changed in more than 10 years as shown by the FY2017 FDA Medical Device Quality Systems Data (Inspections, FDA Form 483 Observations and Warning Letter Citations). CAPA, P&PC and Design Controls consistently account for nearly 80% of the Form 483 observations (note the FDA grouping of CFR clauses under these categories).

It is interesting to note that, while the number of inspections has remained fairly stable, the number of Form 483’s issued has gradually increased. At the same time, the number of Warning Letters has continued to decline since reaching peak levels in 2012-2013, following FDA’s aggressive policy of using these letters as a primary method of influencing compliance beginning in 2008. Warning letters are still issued, but only to firms with systemic QMS issues, severe violations or who fail to implement or follow-through on their corrective action plan in a timely fashion.

The FDA took a more aggressive approach to the issuance of Warning Letters for violative manufacturers beginning in 2008 and reaching a peak in 2012, when 189 Warning Letters were issued, representing a more than 7-fold increase in the annual number of Warning Letters in 2012 compared to 2007

- CDRH Enforcement and Quality Report

This subtle change in approach is intended to drive appropriate action before reaching the warning letter stage. Frequently, warning letters were issued because the agency did not find the violative firm’s response to Form 483 observations to be adequate. This is not the true intent of a warning letter – according to the Regulatory Procedure Manual, warning letters should be issued for violations of regulatory significance; that is those violations that may lead to enforcement action if not promptly and adequately corrected.

FDA appears to have realized that a more effective approach is to interact with the violative firm to evaluate and help develop an appropriate plan of corrective action. According to a Medical Device Enforcement and Quality Report released by the Center for Devices and Radiological Health (CDRH) in November 2018, FDA’s staff review the firm’s responses to the Form 483, provide feedback on the proposed corrective action plans, and monitor progress towards remediation. The result is an increase in the number of untitled letters, which are intended to address violations that do not reach the threshold of regulatory significance to require a warning letter. This approach, along with an increase in the number of regulatory and other meetings, has led to a significant increase in the number of firms found to have corrected observed violations on follow-up inspections.

More recently, FDA has formalized this approach by issuing a draft guidance, Nonbinding Feedback After Certain Food and Drug Administration Inspections of Device Establishments, which can help the violative firm develop and implement more effective corrective actions. To some, it may seem to create a challenge in maintaining objectivity, as the auditor (in this case, the FDA) is also attempting to serve as a consultant. However, if done right, this has the potential to significantly remove waste from the system and accelerate implementation of more effective corrective actions in the QMS to avoid repeat observations in future inspections.

Timely nonbinding feedback can help device firms determine whether proposed actions to address inspectional observations are adequate, possibly avoiding unnecessary investment in potential solutions not likely to satisfactorily address an inspectional observation.

- FDA Draft Guidance

The guidance offers an opportunity to receive non-binding feedback on proposed actions related to FDA observations that involve a public health priority, implicate systemic or major actions or relate to emerging safety issues. If the proposed actions are assessed to be partially adequate or inadequate, FDA will provide recommendations on what additional actions may be required. It is a good opportunity to develop a better understanding of the agency’s rationale for the noted observation(s) and to carefully examine the underlying drivers of non-compliance, which may be affecting other aspects of the QMS not directly covered by the observations. FDA is careful in clarifying that simply following the recommendations does not provide any assurance that regulatory actions will not be taken or additional observations will not be cited. In short, it should not lead to a check the box response; rather it should lead to a more careful examination of the proposed corrective action approach. 

Just as inspecting out defects does not result in fundamental Quality improvement, simply focusing on immediate issues in response to a Form 483 observation or a warning letter does not strengthen the QMS. The main goal of a strong QMS is to consistently help deliver safe and effective products, not just ensure regulatory compliance in audits and inspections. Audits and inspections provide only a snapshot of issues, not necessarily the underlying drivers of non-compliance. A careful and diligent review of the observations is required to adequately develop the corrective action plans. The draft guidance referenced above, from this viewpoint, is an excellent opportunity for device manufacturers.

FDA has recently taken several initiatives to help facilitate a transition from Compliance to a Culture of Quality. Device manufacturers who are able to improve their QMS to achieve and sustain a higher level of Quality can simultaneously benefit from streamlined, accelerated approvals and reduced regulatory compliance oversight. This carrot-and-stick approach by the FDA is illustrated by the Case for Quality (CfQ) Pilot Program, Least Burdensome Provisions and Risk-Based Targeted Inspections.

A changing mindset at the FDA offers a new opportunity for the medical device industry.



Regulatory Procedure Manual, December 2017

FY2017 Annual FDA Medical Device Quality System Data, 2017

Medical Device Enforcement and Quality Report, CDRH, November 2018

FDA Draft Guidance – Nonbinding Feedback after FDA Inspections, February 2019

Case for Quality Pilot Program, December 2017