FDA's The Circulatory System Devices Panel (CSDP, hereinafter referred to as the Panel) held review hearings on August 22 and 23 for two representative products in the RDN field — ReCor Medical’s Paradise uRDN System and Medtronic’s Symplicity Spyral System. Although the Panel's voting results, or recommendations, from the review hearings are not legally binding, the final decision on whether these two products will be officially approved for marketing still rests with the FDA, which will consider the Panel’s recommendations when reviewing the products to make a legally binding decision. It should be noted, however, that the FDA's decisions are generally consistent with the Panel's voting recommendations in most cases.

Vcbeat (WeChat ID: vcbeat) interviewed Professor Wang Jie from Jiangsu Provincial People's Hospital about the results of the above meetings. Professor Wang Jie watched and listened to these two meetings in their entirety.

According to Professor Wang Jie, the hearing from 9 a.m. to 6 p.m. adopted a procedure similar to that of a trial: fair, strict, and transparent.There are four parties involved in the FDA review hearing:Sponsor, FDA officials and professionals, the public, Panel members including those with voting rights and those without voting rights.The Panel includes interventional cardiologists, hypertension specialists, nephrologists, statisticians, public representatives, and industry representatives.The Panel shall have a Chairperson who may cast an additional vote to break a tie in the event of a deadlock during voting on any issue.

The discussion procedure for the two products at the meeting was identical: First, the manufacturer presented the data and then answered questions; afterward, the FDA analyzed the data submitted by the manufacturer and presented their findings on the same set of data, also answering questions—some analytical results might differ from those of the manufacturer. The time allocated to the manufacturer was exactly the same as the time given to the FDA. This was followed by public comments; Panel members questioned the manufacturer; the FDA listed several questions directly related to the three issues for the final vote, asking Panel members for their clear opinions one by one to guide their stance on the final three voting questions.

For example, the FDA asked ReCor and Medtronic 9 and 10 questions respectively. The answers to these questions directly determined the Panel members' opinions on the three major issues of product safety, efficacy, and risk/benefit. After the final vote, each voting member had to explain the reasons for their Yes or No. In this "court trial," the Panel played the role of the "jury," while the Director of FDA's Office of Cardiovascular Devices, Dr. Zuckerman, played a role similar to that of a "judge," but not entirely equivalent to a "judge." His role was to provide explanations and make decisions when discussions involved certain regulatory disputes. The statements from the manufacturers and the FDA were equivalent to the "jury" — the Panel cross-examining both parties.

The voting results (see table below) showed that ReCor Medical's Paradise uRDN System gained clear recognition from the Panel in terms of safety, efficacy, and benefit-risk ratio. The Panel acknowledged the safety and efficacy of Medtronic's Symplicity Spyral System but had lower recognition regarding its benefit-risk ratio.

This resulted in Medtronic losing to ReCor overall. This outcome had a significant impact on the RDN industry, triggering a series of chain reactions and casting concerns and shadows over the further development of the RDN industry.

As is known to all, Medtronic and ReCor Medical’s RDN products adopt completely different technical approaches: the Symplicity Spyral system uses radiofrequency energy for renal artery ablation, while the Paradise uRDN system employs ultrasound energy for renal artery ablation.

Whether the difference in voting results is due to clinical trial data or the superiority of technical approaches significantly influences the direction of industry R&D investment.

FDA Expert Panel Voting Result Statistics (Note: Panel Chair Dr. Lang cast an additional opposing vote in the event of a tie on the benefit-risk ratio for the Symplicity Spyral system, resulting in: 6 votes in favor, 7 votes against, and 1 abstention)

Medtronic has been laying out the RDN treatment for hypertension since 2010. The principle of RDN in treating hypertension is to control elevated blood pressure by blocking sympathetic nerve pathways and adjusting sympathetic nerve activity.

Medtronic estimates that a 1% market penetration represents a $1 billion business opportunity. They forecast global market revenue for this technology to reach at least $500 million by 2026 and at least $2-3 billion by 2030.

However, Medtronic has experienced many twists and turns in the process of developing RDN for the treatment of hypertension.In 2014, the pivotal clinical trial SYMPLICITY-HTN-III for Medtronic's first-generation RDN product failed, showing no difference in blood pressure reduction between the RDN group and the sham control group. This result dealt a heavy blow to confidence in the RDN industry. In 2017, Medtronic introduced a redesigned product and a new clinical trial methodology, continuously releasing positive clinical trial data, which brought renewed momentum to the RDN hypertension treatment sector.

Why hasn't Medtronic, which has returned, gained more positive recognition from experts like ReCor Medical's RDN product?

One of the key reasons is the extremely high execution difficulty of clinical trials for RDN in treating hypertension.Few other cardiovascular disease treatment devices have undergone such long-term and large-scale clinical trials before product launch like RDN, yet still have not been approved for marketing in the United States.

Professor Wang Jie said: "The difficulty in implementing RDN studies lies in the interaction of two confounding factors: the interference of antihypertensive drugs with the blood pressure-lowering effect of RDN and blood pressure measurement.Requiring patients not to adjust medication when their blood pressure exceeds 150 mmHg at enrollment during a six-month clinical trial follow-up period is against patient interests and unethical. Adjusting the medication, however, would prevent the observation of the net effect of RDN on blood pressure.

In addressing this challenge, ReCor pre-specified the blood pressure at 2 months post-procedure as the primary clinical endpoint, as it is feasible to control patients without changing antihypertensive medications within a 2-month period.

Medtronic extended this time frame to 6 months. The results showed that in its On-Med trial, a large number of patients changed medications, leading not only to numerous protocol violations but also causing the 6-month results of the On-Med trial to fall short of the expected clinical endpoint.

Measurement of blood pressure in RND trials also presents significant challenges:We see that ReCor Medical cleverly pre-designed the study with daytime systolic blood pressure from ambulatory blood pressure monitoring as the primary clinical endpoint to address this challenge, significantly reducing the execution difficulty. In contrast, Medtronic chose 24-hour ambulatory systolic blood pressure as the primary clinical endpoint. It can be observed that at 6 months, not only was there significant interference from medications, but also a large amount of missing 24-hour ambulatory blood pressure data due to the high execution difficulty, which led to repeated inquiries from the Panel members on how to handle the missing data.

In 2022, Medtronic reported that in its pivotal clinical trial, the SPYRAL HTN-ON MED Expansion trial, the 6-month follow-up results showed a 6.5 mmHg reduction in 24-hour ambulatory systolic blood pressure in the RDN group and a 4.5 mmHg reduction in the control group (between-group treatment difference: -1.9 mmHg, p=0.119), failing to reach the pre-specified endpoint. They attributed the reasons to the impact of the COVID-19 pandemic, which prevented patients from adhering well to the trial protocol, and patients in the sham control group taking excessive amounts of antihypertensive medications.

Professor Wang Jie believes: "This is precisely the result of underestimating the difficulty of maintaining drug adherence over a six-month period and preventing patients from adjusting their medications. This led to experts continuously questioning Medtronic during the hearing."

Although ReCor’s clinical trials were relatively small in scale, their objectives were clear. Among the three clinical trials conducted, including two Off-Med trials, Radiance II and Radiance-HTN SOLO, and one On-Med trial, Radiance TRIO, the primary efficacy endpoint was the daytime ambulatory systolic blood pressure at two months. According to ReCor’s interpretation, all three trials reached their pre-specified clinical endpoints (see figure below, sourced from ReCor). The consistent results of these three clinical trials indicate that the Paradise uRDN System can safely and effectively reduce patients' blood pressure. This is a key factor for ReCor’s product gaining expert recognition.

Professor Wang Jie believes: "Compared to Medtronic using the 24-hour ambulatory blood pressure change over six months as the endpoint, using the daytime ambulatory systolic blood pressure at two months as the primary efficacy endpoint can better control drug interference. Daytime ambulatory blood pressure is also relatively easier to obtain. Although the number of patients treated with the Paradise uRDN System in ReCor’s three clinical trials did not exceed 300, the design of ReCor's clinical trials clearly demonstrated to the Panel members that the results fully met the expected clinical trial endpoints."

Imagine if Medtronic had set the 24-hour ambulatory systolic blood pressure or even office systolic blood pressure at 3 months as the primary clinical endpoint for its On-Med trial, instead of using the 24-hour ambulatory systolic blood pressure result at 6 months as the primary clinical endpoint. If they had been more patient and waited instead of conducting an interim analysis upon obtaining data from 40 pairs of patients, there is a good chance the results could have been completely different.

Professor Wang Jie further explained: "I believe that Medtronic's setback is due to the flaws in the clinical trial design, not the failure of its RDN radiofrequency ablation system.This conclusion is drawn from the very similar response rates to RDN treatment among hypertensive patients in the ReCor and Medtronic trials (RADIANCE II 64%, SOLO 66%, TRIO 61%; Spyral Off-Med 65%; On-Med 61%. Based on a blood pressure reduction of >5mmHg), especially when comparing the Off-Med results between the two, as this represents the net effect of RDN on blood pressure without drug interference. Another perspective and judgment is that neither the ReCor nor Medtronic On-Med trials reached their pre-set clinical endpoints (per the FDA’s analysis of ReCor TRIO at two months, which did not meet the expected endpoint, see figure below, sourced from the FDA). This outcome also highlights the challenges of conducting On-Med clinical trials for RDN in treating hypertension. Therefore, several members of the Panel repeatedly suggested during discussions that composite clinical endpoints incorporating both blood pressure and medication load should be applied in future trials.

The final voting result of the Panel does not represent the FDA's approval decision on the two RDN devices under review. Overseas analysts believe that Medtronic's RDN Spyral system still has a chance to be approved for marketing. For instance, during the statements after the Panel members' vote, including Chairman Dr. Lange, they expressed that if Medtronic modifies its requested indications, they would change their decision.

Due to the differences in Panel members' approval of ReCor and Medtronic's RDN products, people in China almost unanimously believe that this indicates the superiority of the ultrasound ablation technology route over the radiofrequency ablation technology route, with ReCor’s product achieving better clinical outcomes. Can this conclusion be drawn from the data disclosed at the FDA review meeting?

A large amount of effectiveness data for the Simplicity Spyral system and Paradise uRDN system was presented at the FDA expert hearing, providing us with the possibility to compare the clinical trial data of the two systems.

In the clinical trials without medication from both companies, the results of Medtronic's SPYRAL-HTN OFF MED trial showed,The average 24-hour ambulatory systolic blood pressure in the RDN group decreased by 4.7 mmHg at three months post-procedure, compared to a 0.6 mmHg reduction in the sham control group, with an intergroup difference of -4.1 mmHg.The changes in office systolic blood pressure were: -9.2 mmHg in the RDN group, -2.5 mmHg in the control group, with an intergroup difference of -6.7 mmHg.

Results from ReCor’s RADIANCE SOLO trial showed that at 2 months, the reduction in daytime ambulatory systolic blood pressure was -8.5 mmHg in the RDN group and -2.2 mmHg in the sham group, with an intergroup difference of -6.3 mmHg. The 24-hour ambulatory systolic blood pressure reduction at 2 months was -7.0 mmHg vs -3.1 mmHg, with an intergroup difference of -4.1 mmHg.

Comparing the 24-hour dynamic systolic blood pressure of the two companies, the intergroup difference for ReCor was -4.1 mmHg; for Medtronic, it was also -4.1 mmHg.

According to the data released at the expert review meeting, the between-group difference in daytime ambulatory systolic blood pressure at six months post-operation for Recor was only -3 mmHg between the surgical group and the sham surgery control group, with questionable statistical significance. However, the change in medication load between groups showed a statistically significant difference (p < 0.001). See the figure below.

Therefore, based on the clinical trial data of the two, it cannot be concluded that ultrasound technology is superior to radiofrequency technology.Apart from the blood pressure-lowering effect, ReCor Medical's product did not further increase the patients' antihypertensive response rate (see above). The products of the two companies are at the same level in this indicator. Whether it is ReCor Medical or Medtronic, plc., the response rates in clinical trials were slightly above 60%.

Radiofrequency ablation has been widely used in clinical practice. Ultrasound ablation is not as widely applied in clinical settings as radiofrequency ablation. The challenge faced by ultrasound ablation technology lies in the complexity of product structure and manufacturing processes, including balloons, ultrasound transducers, and cooling systems. In ultrasound balloon catheters, piezoelectric crystals must be properly arranged, and to avoid damaging the vascular anatomy, cooling water needs to circulate within the balloon. This further increases the complexity of the process and manufacturing.

During the two-day long review meeting, what issues in the RDN field did the Panel members think need further resolution?

First is the necessity of ongoing research after market launch.During ReCor's review meeting, the Panel members unanimously and clearly stated that if the RDN device is approved, post-marketing studies will provide further clinical evidence needed to complete the RDN therapy and related technologies, in order to address many of the remaining issues with this therapy, particularly the duration of efficacy and benefits. The Panel members were especially concerned about the safety and effectiveness of using RDN to treat hypertension in minority groups such as the African American population.

Professor Wang Jie also pointed out that post-marketing research and continuous follow-up are very important. We need to establish a complete and long-term chain of evidence from China.

Companies in China should learn from the experience of ReCor and Medtronic, and pay attention to the design and operability of clinical trial protocols.Particularly in two expert meetings, most experts mentioned the drug index, a joint clinical endpoint design combining two indicators: blood pressure and medication. In this aspect, Chinese scholars have taken the lead globally by applying dual clinical endpoints that incorporate both blood pressure and drug load index. They have conducted RCT trials for RDN treatment of hypertension to verify the safety and efficacy of domestically produced RDN products.

As the medical device industry in China continues to develop and reach the global stage, what we should learn is not just technology but also the fair, rigorous, and transparent review process.

The Panel's feedback can help companies developing RDN products improve their products, design reasonable and feasible clinical trials, and address encountered issues, forming a new consensus on how to validate the safety and efficacy of RDN. It is hoped that this detailed process of "observing" foreign peers' thorough evaluation of a cutting-edge product in the cardiovascular field will inspire and promote the research and development of medical devices in China.