October 27, 2020
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Meg Seymour, a senior fellow at the center. Our center analyzes scientific and medical data to provide objective health information to patients, health professionals, and policy makers. We do not accept funding from drug or medical device companies, so I have no conflicts of interest.
This committee is being asked numerous questions regarding whether the data presented is sufficient to support the safety and effectiveness of the Reducer device, and if so, for whom. The device in question is permanent, and therefore should be held to a high standard when considering approval for a permanent device. The FDA Executive Summary points out that “there is a large placebo effect that has been shown in previous blinded studies in the field of refractory angina” including 42% of the sham group in the COSIRA trial. Given this strong placebo effect, a permanent device should not be implanted in patients without demonstrating meaningful improvements for patients compared to an effective sham control group. And, as FDA pointed out, it is important to know if the sham control was effective in blinding most of the patients, so that they did not know if they had the Reducer device. Moreover, the studies must be conducted on a representative sample of patients.
Let’s start with the shortcomings of the patients enrolled in the study. The patients studied are not a representative sample of refractory angina patients:
- More than 25% of patients in the study were on either 1 or no antianginal medications. In other words, they did not have refractory angina.
- There was no information about medication compliance.
- There were no Black or Hispanic patients in the COSIRA trial, and more than 80% of the patients were White or male, or both. White males do not comprise most patients, so it would not be ethical to claim safety and effectiveness for a device that was not tested on most of the types of patients who will use it. And yet, I don’t think the sponsor would be satisfied if the Reducer device was approved only for White men.
In addition to enrollment, the data provided by the sponsor is severely lacking.
- Although there was a statistically significant improvement in the primary efficacy endpoint, we agree with the FDA that the sample was too small to “provide reasonable assurance that the results reflect likely outcomes for most patients.” This raises questions about whether the improvement occurred by chance.
- Only one-third of the patients achieved the level of effectiveness required by the primary endpoint and almost 30% of the patients experienced no change at all from the implant
- The 6-month follow-up period was much too short to evaluate safety or effectiveness for a permanent implant.
- As I previously noted, there was a large placebo effect, which according to FDA “presents challenges for interpreting the data given the limited sample size.”
The bottom line is that the true effectiveness of the device is unknown. We agree with the FDA review that “additional data are needed to identify the patient population most likely to have a clinically meaningful benefit with the Reducer device (considering risks of the implant procedure and the device).”
Now let’s talk a bit more about the safety of the Reducer device. I’m sure you share my concerns, and that of the FDA, that the sponsor did not define a prespecified primary endpoint for safety and instead relied on secondary safety endpoints, such as the successful implant of the device without a need for intervention.
To address some of the shortcomings in the data, the FDA has asked you to discuss and make recommendations regarding the sponsor’s proposal to perform a post-approval randomized sham-controlled trial in a country where Reducer is not approved. That would basically mean that U.S. patients would pay to be experimental test subjects for a product whose risks and benefits are not proven for them – especially for women and non-Whites. Instead, the FDA should require the sponsor applying for approval to do a better job of recruiting patients with refractory angina as well as patients who are female and/or people of color. If they didn’t achieve that when they were trying to get approval, we know the chances are even lower in a post-market study
In summary, we urge the committee to require additional pre-market data from a randomized, properly blinded, sham-controlled study with a representative patient population. Such data are necessary to determine the effectiveness of the device and whether it is worthy of approval, and if so, for whom. The data provided thus far simply do not provide enough evidence that there are benefits outweighing the risks for this permanent device. Additional data are necessary before such consequential conclusions can be drawn.