Medical device manufacturers, did you know there are times when the Center for Devices and Radiological Health (CDRH) will inform the public that FDA has concerns about a marketed device before contacting the company? Why is this? What does CDRH’s signal detection and evaluation process look like and how does the agency engage the various stakeholders?
[Related: Panelists Mark Agostino and Alison Sathe discussed postmarket surveillance requirements under the EU MDR during a recent virtual panel discussion. You can download the full recording here.]
At the FDA/Xavier Health MedCon conference held virtually earlier this year, Associate Director for the Postmarket Program in the 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.”
As background, Yustein referenced a public workshop CDRH hosted in November 2020. “The focus of that meeting was on medical device safety communications. But there really was quite a bit of discussion about postmarket signals. And really, those two processes, signal management, and communications, are really closely linked.”
Although there are multiple types of stakeholders, including patients, clinicians, hospitals, and the media, most of the participants were from industry. The most common theme from Yustein’s perspective was that CDRH should engage impacted manufacturers and clinicians earlier and more often during its evaluation of identified safety signals and in the preparation of safety communications.
CDRH Engages with Manufacturers
Yustein commented that sometimes the agency hears from a company that it was not fully aware FDA was evaluating a safety issue related to its product.
“Here are a few things that if I were working for a manufacturer might cause me to pause and think that FDA has some potential safety concerns, regardless of the time point or where it is coming from. I am not saying all these mean that FDA has started a formal cross-center evaluation, because they can occur at different stages, including the earliest detection phases. These are in no specific order.”
- Safety-related deficiencies that appear in a premarket submission: Although it is uncommon to lead to a formal safety signal from a postmarket standpoint, if the product is already marketed and the submission is making device or labeling modifications, premarket reviewers’ interest in safety issues may arise and you may see some questions in deficiency letters regarding that.
- For those situations where a sponsor is conducting a mandated postmarket study, such as a post-approval study, or a 522 study, deficiency questions that focus on some of the interim and final safety results may indicate that we have some potential concerns.
- Manufacturers often get what are called “Additional Information,” or AI letters, from FDA staff who review medical device reports (MDRs) seeking additional information on the device such as, what happened to the device? What happened to the patient? What happened during the event? In one or more MDRs there may be a signal that an FDA reviewer is looking into what they consider to be a newer, significant safety concern.
- Receipt of an “Information Request Letter” (IRL) from a CDRH safety signal coordinator, and
- Two that are much later in the process—receipt of a compliance letter or directed inspection, or FDA issuing a safety communication or public message.
“I certainly recognize that the public message is not the preferred way to learn that FDA has concerns about a device, but it can happen sometimes for a variety of reasons as the first indicator.”
[Editor’s Note: In the video clip below, medical device experts Mark Agostino and Alison Sathe discuss why companies marketing medical device products to the EU marketplace should take a risk management approach to postmarket surveillance.]
The Information Request Letter
The IRL is one that comes from an Office of Health Technology (OHT) within OPEC when it is evaluating a safety issue that has been entered into the program tracking system and has been assigned to an issue lead and the team has met and started discussing the issue.
“As with most other things we call it a letter, but it will show up as an email,” the CDRH official explained. “We do our best to find the right person at the manufacturer to communicate with, but it is not always as easy as it sounds. Many times, our OHT premarket staff know the main regulatory contacts for the device based on recent submissions. But sometimes we must rely on information in the registration and listing system, and those are not always accurate. Whether either of those sources is the correct contact that the manufacturer would prefer for this kind of communication is not something that we are always sure of.”
An information request letter states that the agency is evaluating a safety issue and is seeking information or data from the manufacturer. It describes the issue and how CDRH became aware of it, what the source of the information was, and then it goes on with a series of one or more questions with a requested response date. Often that is 30 days, but sometimes if the issue is more pressing, the agency may request shorter turnaround times.
Yustein commented that sometimes the agency hears from a company that it was not fully aware FDA was evaluating a safety issue related to its product
The letter does have the name and contact information for the FDA issue lead or safety signal coordinator and “certainly the industry should feel free to contact that person by email or phone should they want some additional clarification or further discussion on the issue or with the questions that are in the letter,” Yustein pointed out. “Upon receipt of the responses and an evaluation by the FDA team, we may certainly have additional new questions, which would then come back to you by a similar process.”
“With any of our processes, there are limitations,” he commented. “I discussed one earlier—finding the right person at the company to correspond with.”
“Two others are related to class signals. One is identifying who the impacted manufacturers are with the limitations of the registration and listing system. Sometimes if a particular product type has numerous manufacturers and numerous models, it is difficult for us to always pin all those down. The other issue we run into is where there are numerous impacted firms as we have limits on what we can do based on what is called the paperwork reduction act.”
Sometimes CDRH may not actually need additional information from the manufacturers themselves as the data it does have could be sufficient to understand the issue and guide the next steps. So, the agency does not send IRLs for all signals.
Safety Communication Process
FDA issues safety communications on some of its signals. They usually take the form of a public safety communication, or “Dear Healthcare Professional” letters, sometimes called a “Dear Doctor” letter. But there are other vehicles, including consumer update Web pages and FDA Voices articles.
The Signal Management Program works closely with and uses CDRH communication experts and risk communication people and their processes. Any recommendation from a signal management team requires concurrence from senior leadership before proceeding with the communication. The final communications also go through leadership clearance before being issued.
We do our best to find the right person at the manufacturer to communicate with, but it is not always as easy as it sounds
Traditionally, the agency tries to call impacted manufacturers at least 24 to 48 hours ahead of posting the communication so that the manufacturers can be prepared.
“During those calls, we typically summarize what the communication will say, when it will be posted and where. This may or may not happen with every communication, especially if we are dealing with large class signals where we are not calling out a specific product by name and we are contacting dozens of manufacturers. In those cases, it is really not practical.”
Interacting with Other Stakeholders
Besides interactions with industry, the agency does have processes to interact with members of the clinical and end-user facility communities.
“During our signal evaluations we have a great breadth of clinical expertise from clinicians within the Center and the agency, but we do occasionally reach out on complicated issues,” Yustein explained.
“We have certainly received a few signals from these communities, but we probably more frequently use them during the refinement process. Often, they help us better understand and characterize the extent and impact of the issue, how it can be identified, prevented, or addressed in real-world settings.”
Some of the methods used include:
- The “Network of Experts” program, which we have in affiliation with multiple professional societies
- Tapping into experts who are Special Government Employees
- Discussion with clinicians or risk managers at user facilities or other government facilities
- The more public advisory committee meeting forum
“We also have newer processes to interact with patients or patient groups. We receive safety signals from individual patients or patient groups either through MDRs, emails, complaints, allegations, and sometimes phone calls. We are looking to improve how we interact more consistently with them during the signal evaluation process.”
The Center has recently set up different vehicles to promote these interactions, including the Patient Engagement Advisory Committee (PEAC), Patient Engagement Conversations, and Patient and Caregiver Connection, which is similar to the network of experts program it uses to interact with professional societies. CDRH also heard at the November meeting in 2020 that patients would like more engagement with FDA during the safety communication process and message testing of safety communications.
CDRH does occasionally interact with or coordinate evaluations and actions with a host of federal health agencies including the CDC, National Institutes of Health, the Consumer Product Safety Commission, and the military, as well as state health departments and regulatory bodies outside of the United States, many of whom it has confidentiality agreements with along with regular meetings.
“I think we all agree that more engagement is better. But at the same time, I think it is important to remember that increased engagement does come at an increased cost as it does require people and time,” Yustein commented.
“It is important to remember that from FDA’s perspective we have many individual companies and groups who are seeking increased engagement with us simultaneously. Throughout this, it is important for FDA to keep a level playing field. This includes the fact that FDA is bound by certain rules about confidentiality and disclosure of nonpublic information, and those sometimes can impede how much we can say to certain parties at certain times.”
[Related: Learn more about postmarket surveillance requirements under the EU MDR by downloading the recording of the recent virtual panel discussion, “Changing Medical Device Regulations.”]
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