Thank you for the opportunity to speak today. My name is Dr. Tracy Rupp: I was previously a clinical pharmacist at Duke University Medical Center and am now a senior fellow at the National Center for Health Research. Our research center analyzes scientific and medical data and provides objective health information to patients, providers and policy makers. Our Center does not accept funding from the drug or medical device industry and I have no conflicts of interest.
We strongly support a drug regulatory process that gets safe and effective new treatments to patients as quickly as possible. Since sugammadex has the ability to quickly reverse the paralysis induced by neuromuscular blockers like rocuronium, it represents an innovative new option to improve surgical recovery. However, as with every new drug, we need to be certain the benefits outweigh the harms. And, the fact that this drug is available in other countries does not necessarily mean it should be available here.
The risks associated with neuromuscular blockade have long been recognized. In a paper in the journal Anesthesiology more than 50 years ago, Dam and Guldmann stated, “Today, the most common cause of postoperative respiratory inadequacy is the use and misuse of muscle relaxant drugs.” Unfortunately, this is still true today.
While currently available neuromuscular blockade drugs carry significant risks, we must be sure that the solution doesn’t create more problems. In August last year, Japan’s Pharmaceuticals and Medical Devices Agency warned that cases of coronary arteriospasm, ventricular fibrillation, and ventricular tachycardia have been reported in patients treated with sugammadex.
In response to the new safety data reviewed today for sugammadex, we make the following observations and recommendations:
- The risk of hypersensitivity is shown to be higher for sugammadex than for other drugs with a propensity to cause anaphylaxis. The rate reported in the literature for anaphylaxis during general anesthesia ranges from 1:3,500 to 1:25,000. At a rate of 0.33%, or 1 in 299, for sugammadex, anaphylaxis can be expected to occur on a regular and relatively frequent basis. As a result, many patients’ lives will be put at risk if this drug is approved.
Furthermore, we don’t know if this estimate of risk is accurate since the Applicant failed to provide a complete description of the extent of the unblinding in the P101 hypersensitivity Clinical Study Report to FDA. Attestations of the statisticians and programmers could not be confirmed due to the deletion of the data files in question, lack of an audit trail of their activities involving the unblinded variable, and the inability to interview all staff involved. Data integrity related to the risk of anaphylaxis has been compromised.
- Sugammadex was not tested in the “cannot intubate, cannot ventilate” emergency scenario and, therefore, should not be approved for this indication. Furthermore, in the non-emergent setting in which it was tested, it achieved the endpoint of T4/T1 equals 0.9 in only 61% of patients in less than 2 minutes. A clinician may use a cavalier technique, under the assumption that sugammadex will save the patient if they get in a bind, but clearly, they cannot rely on sugammadex to help save a patient’s life in this scenario.
- Regarding the proposed indication, “Reversal of moderate or deep neuromuscular blockade induced by rocuronium or vecuronium”: It is important to draw a better boundary around the indication to reflect the population that was actually studied. The drug was studied in non-pregnant, healthy, young patients in a surgical setting. Therefore, if the drug is approved, it should have a much narrower indication of “Reversal of moderate or deep neuromuscular blockade induced by rocuronium or vecuronium in non-pregnant, healthy, young patients in the surgical setting.”
Before sugammadex is approved for use for other types of patients, it must be studied in them. Unfortunately, it is these other types of patients who are most likely to receive sugammadex in the real-world setting. For example, since the drug will be used to reverse paralysis in patients who are difficult to intubate, such as obese patients and pregnant patients, it is essential that these types of patients be studied to make sure it is safe and effective for them. The drug will probably also be used in the ICU setting where patients have multiple co-morbidities, so it is essential to study this population as well. We also need information about the safety and efficacy of the drug in patients with neuromuscular disorders and brain injuries. These patients have a high risk of aspiration and often receive succinylcholine for rapid-sequence intubation. If sugammadex is approved, they are the type of patient who will probably receive it. And yet, we don’t know if the drug is safe for them.
This FDA has rejected sugammadex for approval twice before, for very good reasons. Sometimes FDA Advisory Committees tend to look for a compromise when a sponsor keeps coming back seeking approval for a questionable drug. But to get approval, a sponsor should study the drug on the patients who would need it. They have not done that.
In conclusion, I think you’ll agree that the healthy patient population studied represents only a small fraction of the patients who would need this drug. And, it was not studied in the emergency situations for which it seeks an indication. Add to that the disproportionately high risk of anaphylaxis and trial conduct violations. We urge you to conclude, that given these shortcomings of the data and the many unanswered questions, the overall risk-benefit profile does not support approval of sugammadex.
Thank you for the opportunity to comment today and for consideration of our views.