De Novo Working As Intended: A (Brief) Case Study

By Bob Marshall, Chief Editor, Med Device Online

“Acute lower respiratory tract infections are a persistent and pervasive public health problem. They cause a greater burden of disease worldwide than human immunodeficiency virus infection, malaria, cancer, or heart attacks. In the United States, they cause more disease and death than any other infection, and there has been little change in mortality due to respiratory tract infection for more than five decades,” states an article published in the New England Journal of Medicine by Dr. Joseph P. Mizgerd, a Harvard School of Public Health alum and current director of the Pulmonary Center at Boston University.

One company looking to have a positive impact on lower respiratory tract infections, among other things, is Curetis, a provider of molecular microbiology diagnostic solutions designed to address the global challenge of detecting severe infectious diseases. Curetis has developed the Unyvero System, whose principal focus is to better manage lower respiratory tract infections. Unyvero is a highly automated molecular diagnostic platform with cartridge-based solutions for the rapid and comprehensive detection of pathogens and antimicrobial resistance markers in a range of severe infectious disease indications. Results are available within a few hours, versus days or even weeks when performed with standard diagnostic procedures and equipment.

In April, Curetis received De Novo clearance notification from the FDA to market the Unyvero System and lower respiratory tract infection (LRT) application cartridge in the U.S. I had the opportunity to speak with Curetis' CEO Oliver Schacht and COO Johannes Bacher about their experience dealing with the FDA throughout the still-quite-novel De Novo regulatory pathway.

“Very early on, after we made our submission to the FDA, in one of the first calls we had, some of the senior managers at the FDA basically said – we believe this will be a game-changer – those were their words, not ours,” Schacht said.

Normally, we like to hear those kinds of things when bringing a new product to market. We want to think our product is innovative, disruptive, and will lead to better outcomes and health economic benefits. But in a regulated space like medical devices and diagnostics, it can be the kiss of death. If we truly have a “game-changer,” or a product capable of changing the standard of medical care, the regulatory burden can be very high. Proving safety and efficacy for a superlative product can be much more complicated than doing so for a substantially equivalent "me too" product.

So just how difficult were Curetis’ interactions with the FDA? Quite surprisingly, Curetis did not experience much difficulty at all with their De Novo application.

“The FDA was extremely collaborative and forthcoming with their communication. When you have FDA reviewers willing to do 30-60-minute Skype calls on out-of-office days to discuss an item, to me, that’s truly outstanding,” Schacht explained. “From a European perspective, we always tend to look at our government and scratch our heads and say, 'well they’re civil servants and clearly underpaid,' but not the FDA; they were, for sure, working extremely hard and diligently.”

Bacher also had positive things to say about his experience working on the De Novo submission with the FDA,

“We submitted the De Novo application in January of 2017 and thought it would be out of our hands for a while, but the FDA went into full interactive review within a week or so, and we shot emails back and forth across the Atlantic almost on a daily basis. I hadn’t really expected to get emails from the FDA over a weekend, but I did more than once. They also responded quite swiftly when we had some questions or needed other guidance.” He continued, “One of the larger tasks discussed during the interactive review was the benefit/risk analysis. We collected the data for each and every positive patient sample with the correlated antibiotics data and we were running the data past a group of clinical experts. These experts made judgment calls on what would have changed if they had received the information much earlier. Would there have been a benefit to the patient, or could it have been detrimental? This became the basis of a very thorough benefit/risk analysis and, in the end, helped the FDA to determine the data was acceptable to clear Unyvero for use in patient care in the United States.” 

All of this is very encouraging information for those seeking to market medical devices within the United States. The FDA has been working toward transparency and collaboration with industry, and it is good to hear positive examples in this regard. Schacht also had some positive comments on the timeliness of the review.

“We discussed and agreed with the FDA along the way on best estimates for the review time, and in the end it was literally cleared on day 120 of their 120-day statutory review window, so they used the full review window but came through right on time.” He added, “This clearance will help us tremendously in Europe, in the Middle East, and in Asia as well. Clearing the FDA hurdle, as high as it is, speaks to the quality of the product and the level of validation and rigor it has gone through.”

It certainly is nice to have someone from outside the U.S. recognizing FDA clearance or approval as a major accomplishment from a global perspective. Schacht also related a rather compelling interaction from a face-to-face meeting with the FDA in the second quarter of 2017.

“We met with the agency to discuss some of the clinical data. One of the clinicians from the trial who was in attendance at this meeting described several specific patient cases in the non-interventional trial, comparing the Unyvero LRT results to standard of care (microbiology). Based on chart reviews, the clinician demonstrated representative cases where earlier detection by the LRT assay could have significantly reduced the amount of antibiotics used, as well as cases where the standard-of-care testing had missed clinically important pathogens -- that were positive by the LRT assay -- and the patient had died,” Schacht concluded.

The FDA has a dual charter. They are charged with ensuring medical devices, diagnostics, pharmaceuticals, and biologics are safe and effective for use in the United States. But, they also are responsible for supporting innovation in healthcare. At times, these two pillars of their charter can appear to be in potential conflict with one another. It is great to see an example here where the FDA seems to have struck a proactive balance in fostering safety, efficacy, AND innovation.