Postmarket Medical Device Surveillance at CDRH: Part I

Signal Detection and Management

At the time a medical device is approved or cleared, it has a benefit-risk profile that healthcare providers, patients, and consumers use to make decisions. Device manufacturers work diligently to ensure their products are safe and beneficial as part of the development and application processes.

[Related: Looking for more medical insights? Download the special report, “An In-Depth Look at Combination Product Regulations.”]

However, once a device is on the market, new information—including unanticipated problems and adverse events—may change the benefit-risk profile. FDA is constantly monitoring internal and external signals to assess medical device compliance and decide whether to notify the manufacturer or the public.

What are the public and government signals that FDA monitors for marketed medical devices? How does the agency decide whether to notify the public about an emerging signal? What are the processes and timelines and why is this important to medical device manufacturers?

At the FDA/Xavier Health MedCon conference held virtually earlier this year, Associate Director for the Postmarket Program in the Center for Devices and Radiological Health (CDRH) Office of Product Evaluation and Quality (OPEQ) Ron Yustein addressed these and other questions in a presentation titled, “Postmarket Surveillance and Signal Management at CDRH – Engaging Stakeholders.”

Part 1 of this article covers his discussion of the CDRH Signal Management Program, and Part II details his comments and agency policy regarding engaging stakeholders.

History and Background

Yustein clarified for the audience that he would not be addressing recalls or specific compliance activities.

“There are separate processes, programs, and staff within FDA and CDRH who interact with industry and deal with those issues,” he explained. “Certainly, a recall may be part of a signal or a signal may lead to a recall as one of the action items, but not all signals result in a recall, and recall in and of itself is not necessarily a signal in the type that typically goes through the system that I will talk about, which tends to focus more on issues related to patient or user harm.”

All signals are different and are managed case by case. Rather than getting into specifics, Yustein presented the processes that typically get applied to signals that come into what CDRH calls its Signal Management Program.

The CDRH Associate Director quoted his Center’s mission statement, pointing out the underlined portion regarding assuring continued access to safe, effective, and high-quality products (Figure 1). “To me, the continued access part encompasses the work we do in postmarket surveillance and signal management.”

In 2018, CDRH reemphasized its dedication to postmarket surveillance and signal management in its Medical Device Safety Action Plan. As part of that plan published in November 2018, Dr. Jeffrey Shuren, the Center director, and Dr. Scott Gottlieb, FDA commissioner at the time, publicly stated that CDRH had the goal of working to ensure that FDA was consistently first among regulatory agencies in the world to find and act on safety signals related to medical devices—sometimes referred to at the agency as “first in the world.”

[Editor’s Note: For more on CDRH initiatives, read the author’s April 2, 2020 article, “CDRH Reorganization Takes a Total Product Lifecycle Approach; MDSAP, ISO Adoption, and Collaboration with MDIC Moving Forward.”]

Yustein addressed the sources of information CDRH uses to identify or refine safety signals. He provided a table showing both agency and public information sources (Figure 2).

Included in FDA sources are medical device reports (MDRs), MedSun reports from user facilities, interim and final reports from mandated postmarket studies, submissions for device or labeling changes, allegations or complaints from patients, consumers, clinicians, and more. 

“Public” sources include literature, registered reports or queries, social and traditional media, information from other health or government agencies, and other public sources of information. “There are also some collaborative connections and information manufacturers have that we do not have at a given time and vice versa,” Yustein said.

[Related: Download our latest report, “An In-Depth Look at Combination Product Regulations.”]

The Signal Management Program

Yustein next addressed the Signal Management Program and how his Center deals with signals once they are identified.

After announcing the 2018 medical device safety action plan and its “first in the world” goal, CDRH has been undertaking several efforts to help it meet the stated goals, which the Associate Director said include but are not limited to:

• Getting all staff involved in medical device safety
• Having the staff knowledgeable about how to look for safety issues and raise their hands if they identify any issues, regardless of what type of information they review, whether it is postmarket, premarket compliance, or other
• Developing and utilizing artificial intelligence and machine learning tools to protect and refine signals on top of CDRH, large volume datasets
• Looking for and gaining access to novel sources of surveillance data outside of the traditional ones that the agency has typically relied on like MDRs and postmarket mandated studies
• Having complete postmarketing compliance performance information more available and more readily presented to reviewers and premarket reviewers
• Feeding postmarket information back to premarket and innovation review to hopefully spur innovation and get devices to change for the better in terms of safety

“We work at CDRH to not only develop mitigation strategies to address the acute issue for products that are already on the market and in use but also to feed information back to inform premarket review and hopefully drive innovation towards safer products before they get on the market,” he emphasized. “In other words, one aspect is putting out a fire and the other is trying to prevent fires.”

Yustein presented “a simplistic diagram” of CDRH’s signal management process (Figure 3).

He explained that a “safety signal” is “information which suggests a new potentially causal association or a new aspect of a known association between a medical device and an adverse event or outcome and may warrant further evaluation or action.”

Multiple factors play into determining whether new information represents a signal and not every MDR is a signal.

Also taken into account are other factors, including what is already known or expected in terms of the risks and their rates, the severity of the underlying condition, the device’s benefits, and the risks and benefits of alternative products.

“Calling something at CDRH a signal does not mean that we have concluded the device causes concern or that an action is needed, but rather that we need to pursue further evaluation at that time. I also wanted to point out that a signal can be limited to one product from one manufacturer, or it can have wider implications across one or more device classes or types.”

[Editor’s Note: Learn more about medical device postmarket surveillance requirements under the EU MDR.]

The Signal Evaluation Process

Once a signal is identified by anyone within the Center, the identifier discusses the issue with clinical and management colleagues within their group as to whether a signal should be entered into the agency system for formal evaluation and tracking. If the signal is entered into the electronic system, it is assigned an issue lead, known as a safety signal coordinator, who then assembles a cross-center multidisciplinary team, and the signal then generally proceeds along the path outlined in Figure 3.

Yustein pointed out that the path for signal evaluation is not always linear and the time a signal spends in a given part is not always equal or predictable.

“But in general, after signal entry, we go through what is called our emerging signal notification process and signal refinement, followed by the development of a set of recommendations by the signal team for management review and concurrence, and then implementation of the action plan and reassessments.”

All signals are different and are managed case by case

Within the first 30 days of a signal being entered into the system into our program, agency personnel evaluates whether the public should be notified about the new information even before the evaluation has been completed.

“We certainly believe that there are situations where clinicians’ or patients’ awareness of the information can be important in decision-making even if it is early and we may not have developed a specific recommendation or mitigations yet. We do this through our emerging signal notification process, which was described in our December 2016 guidance. We heard support for this from our patient clinical and consumer groups at our recent November 2020 workshop on CDRH medical device safety communications.”

The team does use an assessment form during this process, which is like what has been published in terms of benefit/risk guidance by CDRH and the team presents its recommendations to senior CDRH leadership. If the leadership concurs, then a 30-day clock begins to issue the safety communication. Since publishing the guidance in 2016, CDRH has issued 16 initial emerging signal notifications and approximately 22 updates through April 2021.

Signal Refinement

“Signal refinement,” Yustein explained, “is the process where we look to gather or analyze additional information from other data sources beyond the index source of the signal. It is also a time to try to determine if the issue applies to other similar devices from other manufacturers or device types with similar design, intended use, or components.”

Many of the sources used to refine a signal are identical to those from the initial signal. It is common for a data source to serve as both a signal generator or detection source as well as a refinement source.

For most of the signals, agency personnel also reach out to the sponsors to obtain information from them due to the variability in the quality, quantity, and ability to access relevant data and the time it can take to identify and collect that information. The refinement stage can sometimes require significant time and resources, the CDRH official said.

As the team is reviewing information, it is keeping an eye on whether there might be appropriate mitigation actions to pursue either by FDA, the manufacturer, or both. The team develops its recommendations and presents them to leadership for concurrence.

“There are numerous regulatory and/or public health actions that we can take or that we may ask manufacturers to take in response to a signal. For any given signal, we may decide that one action, more than one action, or even no action is warranted at the time.”

Public communications and labeling are two of the more common outputs of the Signal Management Program at CDRH. In addition, there are signals that get entered into the agency system and undergo formal evaluation, but for which the team believes no action is required at that time. Those signals usually end up going into a regular periodic monitoring mode. About 25% of the signals that come into CDRH’s system end up in that category.

In the next installment of this article, Yustein provides details regarding how the agency engages stakeholders, including patients, clinicians, hospitals, and the media.

[Related: How will the new EU Medical Device Regulation affect combination products? Download our latest report to find out.]