Thank you for the opportunity to speak today. I am Dr. Danielle Shapiro, I am a physician and senior fellow at the National Center for Health Research. Our research center scrutinizes scientific and medical data and provides objective health information to patients, providers and policy makers. Those are the perspectives I bring with me today. We do not accept funding from the pharmaceutical industry and therefore I have no conflicts of interest.
It is imperative to address the root causes of pain and opportunities to safely prevent and treat it. Helping patients avoid opioids in the postoperative period may prevent pain conversion from acute to chronic pain, and also avoid opioid addiction. In order to achieve these two goals, opioid-sparing pain medications must be safe and effective in the postoperative period. Analgesics such as Exparel may be the answer, but based on the available data, there is insufficient evidence to recommend supplemental approval.
The sponsor has failed to adequately demonstrate efficacy supporting the proposed supplemental indications. Half of the clinical trials showed no significant benefit. Neither trial C-322 (the intercostal block) nor trial C-326 (the femoral block) demonstrates adequate evidence that this drug works for individual nerve blocks. The other trials suggest potential efficacy for brachial plexus or femoral block. However, given the mixed results from the two femoral block studies, it is possible that demonstrated efficacy in one instance was due to chance. Additional studies which include active-comparator arms are needed to provide conclusive evidence. The sponsor should be required to replicate positive results before the drug is approved for this indication. The post-hoc analysis on C-326, should be taken as exploratory analysis, rather than a true demonstration of efficacy.
In addition, the sponsor has not provided sufficient data to support a broad indication for nerve block. The phase II C-203 study (ankle block) favored immediate-release bupivacaine over 350 mg Exparel, and it is unlikely that the lower doses would work. Because the pharmacokinetics of this drug vary so widely based on selected block site, it is likely that its efficacy also varies. For that reason, the Sponsor should be required to demonstrate efficacy for each identified individual nerve block site.
In addition to concerns about efficacy, we are concerned about the safety of this drug. The OSE findings demonstrate an association between Exparel and local anesthetic systemic toxicity (LAST). Furthermore, knee replacement patients were more likely to fall in trial C-326’s treatment arm. Given that early mobility is the key to recovery following joint replacement surgery, an inpatient fall is counterproductive at best, discouraging patients from walking after surgery. We agree with the sponsor that such patients should not be given Exparel, and if Exparel is eventually approved after more conclusive data are provided, this warning should be clearly marked as a contraindication on the label. Finally, because the pharmacokinetics of this drug vary so widely based on selected block site and technique, and the PK data are unavailable for other sites, there is insufficient data to establish dosages for any chosen nerve block that best achieves a balance of therapeutic efficacy and safety.
In conclusion, we need post-surgical pain treatments that spare patients from opioid use. However, at this time, the data are insufficient to recommend supplemental approval of Exparel. The evidence must be replicated in well-designed studies, including controlled studies with active-comparator arms. Currently the data are inadequate to support a change in the product indication or label.
Thank you for the opportunity to share our perspective.
The US Food and Drug Administration’s (FDA’s) Anesthetic and Analgesic Drug Products Advisory Committee voted 6 to 4 against approval of bupivacaine liposomal injectable suspension (Exparel) as a nerve block to treat regional postoperative pain.
See additional news media coverage here.