Warning letters issued by FDA to medical device manufacturers are a significant concern that can mean challenging times ahead for the manufacturer. Warning letters certainly have a negative stigma attached, and for good reason, as they are quite often a sign of on-going issues that urgently need to be addressed to protect the safety of patients using the device under review. For other manufacturers in the medical device sector, these letters can serve as an opportunity for self-assessment and improvement, as they provide further clarification regarding how FDA interprets regulations and standards.
FDA Warning Letter (WL) CMS 617539 was a significant escalation of previously highlighted concerns regarding a wide range of issues and provides several regulatory areas to review and opportunities to learn. Our goal was to analyze and discuss significant findings in WL CMS 617539 so learnings can be shared with a broader audience. The Medtronic Diabetes unit has several significant, but not insurmountable, challenges to address. The issues identified here are much more serious than the typical implications of receiving a WL. Further to this, some of the language in the letter, and actions taken by FDA, suggests a possible concern with the FDA’s level of trust in the Medtronic Diabetes unit.
Summary:
The FDA WL CMS 617539 was posted here on 28 December 2021. This letter highlights and describes several gaps within the Medtronic Diabetes quality management system; CAPA, Risk Management, Complaints and MDR. Coincidentally, these are gaps that are also frequently identified by FDA during audits (See FDA 2020 summary and FDA 2021 summary). Further, the WL states Medtronic Minimed 600 series insulin infusion pumps are adulterated and misbranded; adulterated due to CGMP (21 CFR 820) gaps, misbranded due to labelling not containing appropriate medical device reporting (MDR, 21 CFR 803) detail. FDA presented the WL after five successive responses were provided to address FDA concerns raised in the July 2021 483.
High-Level Chain of Events:
The root of the problem begins in 2016, Medtronic opened CAPA 299677 in June 2016 to address increased complaints regarding damaged clear retainer rings. These damaged retainer rings can lead to an over- or under-dose of insulin potentially causing serious adverse events, including death.
Pumps with the clear retainer rings were under a Class I recall (the most serious) as of 21 November 2019 after the replacement black retainer rings were commercialized in August 2019.
Medtronic closed CAPA 299677 a few months after commercializing the black retainer rings, which was just before the recall (21 November 2019) was initiated against pumps with clear retainer rings.
There are currently several open recalls against the Medtronic Minimed 600 series pumps; some of which center around the defective clear retainer rings.
The 09 December 2021 WL CMS 617539 is an escalation of the 07 July 2021 483 after five separate successive responses from Medtronic.
FDA concerns:
FDA noted gaps against several parts of the CAPA regulation in 21 CFR 820.100, including:
820.100(1) Analyze all sources of quality data. FDA has been on record about these concerns for many years. Some know the sources chart contained in the link as “Big C - Little C.”
820.100(3) Identify actions to correct nonconforming product. FDA reported that Medtronic did not remove the pumps with the defective retainer ring from the field due to underestimating the risk, hence nonconforming product was not corrected.
820.100(4) V&V changes to ensure corrective and preventive actions are effective AND did not adversely affect the finished device. There are many complaints against the replacement black retainer rings (877), suggesting the root cause of the defective clear retainer ring may not have been adequately addressed.
820.100(5) Implementing and recording changes in methods and procedures to correct and prevent identified quality issues. Medtronic failed to remove all recalled product from the field, despite the availability of the replacement black retainer ring.
Medtronic may have been hasty in closing CAPA 299677 approximately two months (August 2019 - Oct 2019) after fielding the replacement black retainer ring, especially considering the numerous complaints against the pumps with the black retainer ring.
FDA also documented concerns regarding Medtronic’s approach to risk assessment and its implications:
The CAPA System procedure refers to the Product Risk Management Process (SOP104-08) to conduct risk assessment activities. FDA states Medtronic has underestimated the probability of occurrence of the potential harm due to damaged retainer rings. Consequently, the assigned risk was lower than it should be, and no correction or removal was initiated to remove defective devices from the field. This was in June 2016.
Jumping ahead to March 2021, and 15 revisions of the Product Risk Management Process SOP later, the formula for the risk calculation was updated, but was still deemed inaccurate by FDA. This was due to using the total product shipped instead of total product in use for the denominator to calculate probability of occurrence. Also, the risk threshold was changed necessitating higher probability of occurrence for a higher severity harm to be assigned. Both served to continue to underestimate the risk of harm due to defective retainer rings, despite the reality of 74,000 total complaints (57,000 MDRs uploaded) against the defective retainer rings between July 2016 and the initiation of the recall in November 2019. Was Medtronic updating their residual probability of occurrence to track the rate of field complaints?
FDA noted the Medtronic Hazards Analysis was incomplete and the suitability of the risk acceptability criteria was based only on the mortality rate associated with type 1 diabetes and did not account for other adverse events such as severe hypoglycemia and diabetic ketoacidosis, which can also present serious harms. The focus on mortality rates only led to a down classification of the risk severity. FDA noted Medtronic underestimated the risk from damaged retainer rings due to using the number of products shipped rather than the number of products in use, thus artificially reducing the probability of occurrence. Combined with having an artificially reduced severity due to an incomplete hazards analysis, the risk was understated.
As far as investigating complaints (820.198(c)), Medtronic confounded the investigation of the defective clear retainer ring with the black retainer ring. FDA noted this occurred when closing complaints against the black retainer ring without a solid justification, and including them as resolved due to the findings of the investigation into the defective clear retainer ring, which is not appropriate. Additional lapses in performing an investigation of complaints were noted for a potential cybersecurity incident, glucose sensor failures and issues with Carelink software.
Regarding the FDA concern that these pumps are misbranded, FDA stated Medtronic failed to provide MDR data when required (labelling lacked necessary disclosures). Failure to upload an MDR was noted when Medtronic became aware of information that reasonably suggested that a marketed device may have caused or contributed to a death or injury (803.50(a)) and that a malfunctioned device may have caused or contributed to a death or serious injury (820.50(a)(2)). The latter malfunction is the same subject as the recall. This is a curious gap considering the posting of an MDR does not equate to admitting the device failure caused the adverse event.
FDA is withholding final judgment on Medtronic responses until they are implemented and proven effective.
Recommendations - what Medtronic management should implement immediately:
Medtronic needs to look outward. Medtronic should consider being more sensitive to the FDA’s increased level of concern which was reflected in at least three areas:
FDA’s insistence that the risks due to defective retainer ring were underestimated and Medtronic delayed acknowledgment of the same ultimately resulting in a recall 3.5 years later. After 57,000 more MDRs.
Medtronic’s multiple partial and perhaps in the FDA’s eyes inadequate responses after the July 2021 483 and FDA’s presentation of the warning letter one week after Medtronic’s fifth response.
The length of an inspection itself is often indicative of a negative outcome. Quality system inspections typically last one to two weeks (mode is 4 days based on five years of published warning letter data), Medtronic’s inspection lasted twice as long. In general, longer inspections do not turn out well for the manufacturer and indicate underlying issues are to blame.
A frayed relationship with FDA or any regulatory body will never benefit a medical device manufacturer. Medtronic should consider investing some goodwill in the relationship.
Medtronic needs to look inward. Developing and sustaining medical devices in the marketplace is not for the fainthearted. Rigor and attention to detail must be ever present even when the task is difficult and/or routine. Medtronic appears to have numerous lapses across the organization, including;
Failure to execute all the necessary steps in their CAPA (FDA basically did a gap analysis on Medtronic’s CAPA process and found it lacking, so it should be remediated immediately) and recall processes (Quality, Regulatory),
Unjustified changes to the risk zones and severities (Quality, Clinical),
Gaps in their hazard analysis and probability of occurrence calculations (Quality, Clinical),
Inadequate redesign of the retainer ring (R&D (Design Control), Quality),
Inadequate evaluation of the effectiveness of the retainer ring redesign (R&D (Verification effectiveness, Design Review), Quality)
Failure to investigate complaints appropriately and efficiently (Quality, R&D) and
Failure to report adverse events in a timely manner (Regulatory).
Together, these suggest possible systemic and cultural issue at the Medtronic Diabetes unit. FDA may be thinking the same thing.
For the rest of us, how can we benefit from awareness of Medtronic’s troubles?
Be thorough in design reviews. Sometimes, designs reviews collapse to re-review of documents and/or focusing on getting a green light to the next phase, i.e., staying on schedule. Fight complacency and do the work of challenging assumptions, ensuring explanations are comprehensive and, of course, ensuring the design being reviewed is indeed safe and effective.
Provide all relevant information to the Site Quality Representative, and any other relevant management representatives to ensure they are in alignment with the plan . It is the management representative’s responsibility to ensure quality system requirements are established and maintained. Periodic management reviews should cover all parts of the quality system. Any status, concerns, risks, needs, or delays should be documented and shared along with recommendations and requests so appropriate actions can be taken.
Conduct rigorous internal audits. Ideally, internal audits should be a dry run of an actual audit done by an objective 3rd party instead of a cursory check of a colleague’s area of responsibility. Internal audits should be seen as a tool for identifying opportunities for improvement and potentially helping actual audits go smoother. Quickly develop and document plans to address any identified gaps.
Be comprehensive, methodical, and thorough when conducting a risk analysis. Seek and consider cross functional input to ensure risk analyses are comprehensive and optimal risk controls are identified, implemented and verified. Take the time to ensure team members have a common and complete understanding of the product design and use. Seek medical/clinical expertise as early in the project as possible to ensure a comprehensive hazards analysis is available.
Proactively manage your external regulatory relationships. A manufacturer’s regulatory affairs team needs to regularly communicate with FDA and other regulatory bodies. A solid relationship, even if there are some difficulties, will bring benefits and build goodwill. Sharing plans, updates, seeking input and being responsive to requests all serve to make solving future difficulties a bit easier.
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