NCHR Testimony at FDA about Buprenorphine Sublingual Spray, Buvaya

Megan Polanin, National Center for Health Research: May 22, 2018

Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Megan Polanin. Our research center analyzes scientific and medical data and provides objective health information to patients, providers, and policymakers. We do not accept funding from industry, so I have no conflicts of interest.

As with any other drug the FDA evaluates, opioids should be held to a high standard for approval. Given the well-known risks and high rates of misuse and abuse, I think we can all agree that we should practice extra caution with opioids.

Please consider these questions as you evaluate Buvaya’s benefit/risk ratio:

1) Should the FDA approve new opioid products with unknown risks of abuse?

Commissioner Gottlieb has stated that it is critical that the FDA promotes the development and encourages use of opioids that are harder to manipulate and abuse over opioids that do not offer any forms of abuse deterrence. Buvaya was not intended to be an abuse-deterrent formulation and does not have any abuse-deterrent properties and thus does NOT align with this goal.

The sponsor has stated that this drug has a lower potential for abuse compared with other opioids. However, they have not provided evidence to support that claim. By now we should know not to assume a product is less likely to be abused unless there is evidence involving patients to support that assumption.

2) Do the benefits of Buvaya outweigh its risks?

This drug is intended to help patients with acute pain. Results of Study 062 demonstrated that Buvaya can reduce patients’ pain intensity and benefit pain relief. However, it did not contribute to meaningful pain relief.

Most of the patients administered either of the two lower doses of this drug (0.125mg/0.25mg) never experienced meaningful pain relief! In order to experience meaningful pain relief, more than one third of patients took an additional dose of Buvaya or a rescue drug. The higher dose also had problems. As the FDA pointed out, patients reasonably expect pain relief within an hour of taking the first dose. However, the median time to meaningful pain relief for patients on the higher dose (0.5mg) was an hour and a half. [That means half didn’t have meaningful pain relief for over 90 minutes.]

We agree with the FDA that this makes it more likely that patients would take an extra dose or use another opioid before the recommended time for the next Buvaya dose. This could increase the risk of adverse opioid-related events or even overdose.

Regarding adverse events, the rate of nausea, vomiting, and dizziness were higher for Buvaya compared to opioids used in similar acute pain settings. In addition, if opioid-naive patients experience clinically significant respiratory depression, this drug could make symptoms worse. If this occurs, the FDA noted that standard doses of naloxone are not sufficient to reverse buprenorphine-induced respiratory depression.

3) What are the potential unintended harms of Buvaya in the real world?

We are concerned that several factors could potentially lead to inadvertent misuse/abuse of Buvaya:

  1. A spray medication might be misinterpreted as less dangerous than an opioid pill. Patients may be less apt to consider the serious risks of administering an opioid spray and less concerned about using a higher than recommended dose.

  2. Taking this drug is very easy. Patients may not perceive the spray as drug-taking behavior (as compared with taking a pill or placing a patch). As a result, patients may be less likely to remember when they last took the drug and less worried about taking the next dose too soon.

  3. This drug does not work quickly to meaningfully relieve pain, even at the highest dose. This may influence patients to take more of the drug or another rescue medication sooner or more often than they should to adequately relieve their pain.

  4. As patients who would take this drug are likely to be opioid-naive, they will seemingly have less knowledge and experience with opioids and thus be more susceptible to these real-world risks.

The FDA reported that available data provide very limited insight regarding the risks of misuse, abuse, or overdose associated with Buvaya compared with other buprenorphine products or opioid analgesics.

In addition to the poor efficacy and unknown yet potentially high risk of overuse, it is not clear that the novel delivery mechanism will greatly help patients. Only about 5% of dispensed prescriptions for buprenorphine and buprenorphine-naloxone products were for drugs indicated for pain management; most were for products indicated for treating opioid dependence. Of those for pain management, the vast majority of prescriptions (87%) were dispensed for the buprenorphine transdermal patch and only 13% for the buprenorphine buccal film. Thus, it is questionable how many patients will benefit from a sublingual spray form of buprenorphine.

In conclusion, opioids can be greatly beneficial and, as we all know too well, can also produce tremendous harms for patients suffering from pain. Buvaya presents concerning safety issues, its benefits seem minimal, and the delayed benefit for patients may result in overuse or misuse in the real world. Please carefully consider the risks of putting another non-abuse-deterrent opioid on the market and whether the sponsor’s attempts to reduce misuse and abuse are sufficient. We do not think so and more important, there is no evidence demonstrating that this product will be misused less often than other opioids. We therefore urge you to vote that the benefits of Buvaya do not outweigh its risks.

Thank you for the opportunity to share our perspective.

The Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) and the Drug Safety and Risk Management Advisory Committee (DSaRM) voted 18-1 against approval of Buvaya. Read more about the meeting here.