FDA Issues Product Safety Recommendations

The Food and Drug Administration (FDA) recently convened meetings on three important patient safety issues. Here’s what members need to know …

Paclitaxel-coated Devices & Late-mortality Safety Signal

These coated products—paclitaxel-coated balloons and paclitaxel-eluting stents—are used to treat peripheral arterial disease in the femoropopliteal arteries.

On June 19–20, 2019, the FDA’s Circulatory Systems Device Panel met to discuss and make recommendations on the late-mortality safety signal associated with paclitaxel-coated products. The FDA warned that using these devices may increase mortality risk after two to five years. The warning was based on an analysis that looked at 28 randomized controlled trials with 4,663 patients with peripheral arterial disease who had been treated with paclitaxel-eluting stents or paclitaxel-coated balloons.

Background

• 2012 – The FDA approved the first of these devices, which was the first paclitaxel-eluting peripheral stent

• 2018 – The FDA approved the last of the five total devices currently on the market, which included three peripheral balloons and two peripheral stents

Findings from the Katsanos meta-analysis suggested an increased mortality rate in patients who received peripheral arterial disease (PAD) treatment with the paclitaxel-coated devices and prompted the FDA to re-evaluate the products. The study was published in the Journal of the American Heart Association (Dec. 2018) and showed that patient mortality rates at two years “significantly increased” and then “increased further” up to five years after the use of paclitaxel-coated balloons or paclitaxel-eluting stents versus uncoated devices.

• June 2019 – Summary comments from the two-day meeting included:

• Data limitations from the meta-analysis prevented confirmation that the late mortality signal represented a class effect among the devices. Available data was unable to exclude any device from the group

• The panel was unable to identify a particular cause of death to explain the late mortality signal in patients treated with these devices

• Observed rates of both cardiovascular and non-cardiovascular death were higher in patients treated with paclitaxel-coated devices vs. uncoated devices

• The panel agreed that FDA should continue to approve devices with 12-month clinical data that demonstrated an assurance of safety and effectiveness, but FDA should strengthen post-approval conditions to ensure adequate data collection for potential signal detection

• The short-term benefits of paclitaxel-coated devices continue to outweigh the risks, and the devices should not be removed from the market. All agreed that risks should be communicated to the patient to support an informed choice, with some noting that treatment decisions should be left up to the patient and treating physician

• Recommendations for devices for the superior femoral artery should also apply to clinical studies, informed consent and labeling for paclitaxel-coated devices used in other indications, such as AV fistula and chronic limb ischemia. The panel remarked that the benefit-risk profile for these patients may be different given the high mortality rates for such patients within two to three years

• The industry should collaborate with the FDA on future study design efforts to evaluate the late mortality signal, including adding language to the labeling (e.g., instructions for use) for vascular paclitaxel-coated devices to indicate the presence of a potential late-mortality risk as well as the potential benefits

Outcome: The FDA panel will review these recommendations and provide direction on the use of these devices through a public statement. HealthTrust will share the recommendations with its members. View summary document here.

Surgical Staplers for Internal Use Changed to Class II Devices

Whether manual or power-driven, these devices are used most often in minimally invasive surgeries to cut and quickly seal vessels and tissues inside the body.

On May 30, 2019, the General and Plastic Surgery Devices Panel of the Medical Device Advisory Committee met to discuss and make recommendations regarding the reclassification of surgical stapler devices for internal use from Class I (general controls) to Class II (special controls). According to Kaiser Health News, the FDA acknowledged that more than 56K surgical stapler malfunctions were not recorded in its traditional public reporting system* in a seven-year timespan (from 2011 through 2018). Risks with the devices include severe surgical complications, including sepsis, bleeding, the need for a permanent ostomy bag, lasting nutritional and digestive issues, a leak in the closure (anastomotic leak), the need for additional closures (anastomoses) or additional surgeries, and in worst case, death.

*The Manufacturer and User Facility Device Experience (MAUDE) database houses medical device reports (MDRs) submitted to the FDA by both “voluntary” reporters (e.g., healthcare professionals, patients and consumers) and “mandatory” reporters (e.g., manufacturers, importers and device user facilities). 

Background

• 1997 – The FDA created a program known as “alternative summary reporting” to collect data for more efficient internal review of well-known risks. Medical device manufacturers could apply for an FDA exemption to prevent specific incidents from going on the public FDA database

• 2017 – The alternative summary reporting program was updated to promote greater public transparency and only low-risk products were eligible for the alternative reporting method

• March 2019 – In a letter to physicians, the FDA acknowledged that “many more device malfunction reports” were reported to the agency than it had previously publicly disclosed. The total number reported (from 2011 to 2018) was actually more than double, totaling close to 110,000 malfunctions or injuries, when taking nonpublic reports into account

• April 2019 – Publication of the proposed reclassification order

• May 2019 – The FDA ends the alternative summary reporting program; device makers will be required to file individual reports documenting each case of device-related patient harm 

Outcome: The FDA’s Advisory panel unanimously recommended the reclassification of surgical staplers for internal use from Class I (general controls) to Class II (special controls). View summary document here.

Absorbable Collagen-based Hemostatic Devices Downgraded to Class II 

These products facilitate hemostasis by speeding up the clotting of blood 

On May 31, 2019, the FDA General and Plastic Surgery Devices Panel of the Medical Device Advisory Committee met to discuss and make recommendations regarding the reclassification of absorbable collagen-based hemostatic devices from Class III (pre-market approval) to Class II (special controls). Primarily applied during surgical procedures, these products and devices control bleeding that has not responded to more traditional methods such as ligation or cautery or cannot be controlled due to inaccessibility. Currently these products fall into three groups:

• Absorbable Hemostatic – Collagen based

• Absorbable Hemostatic – Non-collagen based

• Absorbable Collagen Hemostatic Agent with Thrombin

These products come in various forms such as powders, sponges and sheets. HealthTrust offers contracted products within all three groups. The FDA panel discussion primarily focused on the absorbable hemostatic collagen-based products. 

A comprehensive list of risks specific to absorbable collagen-based hemostatic devices, such as infection, foreign-body or adverse tissue reaction, failure to be absorbed, embolization, hematoma and others, extracted from reports received by the FDA via the MAUDE database were discussed in detail. The panel felt that based upon the valid scientific evidence available, primarily from premarket clinical trials and a long history of safe and effective use, reasonable assurance of safety and effectiveness for these products remained.

The FDA proposed several special controls that would further provide reasonable assurance of safety and effectiveness as well as mitigate risk, including material characterization, biocompatibility, performance data for sterility and shelf life, labeling and others. They did not feel that different special controls were needed for different forms of the device (powder, sheet, etc.).

Outcome: The panel recommended a move from Class III to Class II for absorbable collagen-based hemostatic devices intended to be placed in the body during surgery for the purpose of producing hemostasis by accelerating the clotting time. View summary document here.

Note: Absorbable hemostatic collagen-based devices containing added biologics, and absorbable hemostatic non-collagen-based devices, are outside the scope of this proposed reclassification. Those devices, which are for a use that is of substantial importance in preventing impairment of human health, will remain Class III devices pursuant to section 520(l)(1), as the FDA has neither received nor identified sufficient evidence from nonclinical or clinical studies to establish special controls to provide a reasonable assurance of their safety and effectiveness.

For questions on these or other FDA topics, contact HealthTrust’s Clinical Research team through physicians@healthtrustpg.com.

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