Stephanie Fox-Rawlings, PhD, National Center for Health Research, January 16, 2020
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Stephanie Fox-Rawlings, the Center’s Research Manager. 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.
We can all agree that pain relief after surgery is important for patient recovery. Local pain relief that reduces opioid use, reduces adverse events resulting from systemic exposure, and improves recovery would be helpful. However, the evidence presented for this meeting does not demonstrate that SABER-bupivacaine [Posimir] fulfills these goals.
Only 2 of the randomized, controlled clinical trials that tested efficacy had statistically significant reductions in pain compared to placebo. Keep in mind that 6 other randomized, controlled trials did not show greater reductions in pain. The sponsor briefing materials stated that they defined only the two trials that showed benefit as pivotal because their primary endpoint showed a significant benefit, but in fact pivotal trials should be defined by their intent to demonstrate efficacy and safety – not by their success in demonstrating benefit.
It is not clear if there were differences in the trials that would explain the differences in results. The drug application method was not the determining factor nor was the type of surgery.
One possible explanation is that the drug has little effect over placebo. Even when the drug was statistically more beneficial than placebo, the benefit was very small and not necessarily clinically meaningful. At best, the difference between drug and placebo was only 1.1 to 1.3 points on an 11-point scale. There are many possible reasons for that difference: differences between health care practices or different selection of patients just to name two. In addition, the small number of people in some treatment arms or other aspects of the trial design could have affected the results, making it impossible to be certain the difference was not due to chance.
And as I mentioned, the only studies with statistically significant differences were conducted outside the U.S., while the PERSIST trial, which was conducted in the U.S. did not have a statistically significantly difference in pain. And other studies conducted outside the U.S. didn’t have significant results either. Since the FDA’s mission is for drugs and devices to be used in the U.S., the lack of efficacy for U.S. patients is a serious shortcoming in the application.
It is also important that the patients in all of these trials were almost all younger and white – especially those not in the U.S. That is a serious flaw in the study design, unless the sponsor is planning to ask for approval only for younger, white patients.
If the drug reduced opioid use and sped recovery, that would be beneficial. However, only one of the two trials indicating a significant reduction in pain also had a reduction in opioid use. Neither of the studies that found pain reductions demonstrated faster recovery or improved function.
Given the questionable and at best small benefit, the FDA raised concerns about the drug’s safety profile, including effects on the nervous system and drug toxicity.
Long-term safety is of particular concern. We have seen cases where a drug can cause long-term adverse events, sometimes in surprising ways. In this case, nonclinical studies indicate that residues can remain in a patient’s body for a year, and local adverse events suggest that it affects the tissue where it is applied. The newly supplied analyses and PERSIST trial do not fully address these concerns . We also need to consider that new adverse events may be discovered if used in a more diverse population in terms of age, race, or ethnicity.
In summary, there is not good evidence that SABER-bupivacaine provides a meaningful benefit to patients, and certainly not proven that the benefits outweigh the possible risks. Most important, the sponsor has not proven that this formulation of the drug works better or is safer than the opioid, bupivacaine. Bupivacaine itself has been on the market for decades, is available as a generic, and does not have these new safety concerns. Thus, there is no reason to approve this drug just to have “another tool” when there is no evidence that it is a better tool than currently available options.
The Anesthetic and Analgesic Drug Products Advisory Committee vote was split on the issue of whether the Posimir (SABER-bupivacaine ) should be approved. Six members of the committee voted for approval and six voted against approval.