Thank you for the opportunity to speak today. My name is Dr. Danielle Shapiro. I am a physician and 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 policymakers. We do not accept funding from industry, so I have no conflicts of interest.
Buprenorphine can play a critical role in the treatment of opioid use disorders. The FDA and this Advisory Committee are faced with precedent-setting decisions that will affect millions of individuals with opioid use disorder.
We have concerns about the efficacy of this drug. First, we only know how this drug performs in comparison to no drug at all and only when following a period of stabilization. That stabilization period would not be typical of how it would be used in the real world. There was a statistically significant benefit of the drug compared to placebo – almost identical whether they were taking 300/100mg and 300/300mg doses.
But for the results that really matter, the efficacy was not at all impressive. Unfortunately, only 12-13% of treated participants were considered 100% abstaining from using opioids compared to 1% taking placebo. Even using the lower standard of abstaining 80% of the time, only 28-29% of treated participants did so.
These results are not nearly as good as other products already on the market. For example, on the label for the approved modified-release buprenorphine drug, Probuphine, it reports 63% of participants achieving 100% abstinence, using similar measures for 100%.
The blockade 13-0002 study indicated that the drug may not be effective at reducing craving for very potent opioids. That’s an important outcome and the drug did not do well.
A key question is: What does 80% abstinence look like in the real world? If the patients were still taking opioids, and lying about it, more than 20% of the time while in a 24-week clinical trial, what will happen when the trial is over? Will they be back taking drugs at 6 months or 9 months or 12 months? If an individual is abstinent approximately 80% of the time during the 24 weeks of a clinical trial, is that good enough to keep them off drugs long-term? We don’t know the answer to these questions.
In addition, the research was conducted in a way that could easily bias the results. Urine samples were scheduled — not random — once weekly. This gave participants the opportunity to cheat. And, the researchers combined self-reported drug use and urine drug screen results, even though many times patients reported no drug use when their urine sample tested positive. Why include self-reports knowing they were often inaccurate.
I’m sure you’re wondering about this drug’s long-term effects. How long will patients need to take this drug to maintain abstinence?
Regarding safety, there is a lot that we don’t know. The sponsor did not collect important data about the drug’s effect in those with liver or kidney impairment, the interaction of the drug with other drugs, and the animal effects of IV administration. For example, the in vitro clotting of dog blood is frightening. Accidental or intentional IV administration of this drug has the potential to be deadly. Further, this drug’s packaging with a syringe and needle creates a high abuse potential and, consequently, a grave safety risk.
In addition, we don’t know about the actual cardiac safety of this drug. If it has the potential to prolong the QT interval, it has the potential to put patients into lethal heart rhythms, and those risks would be further compounded by other drugs that patients are likely to be taking, including antipsychotics.
Clearly the 300/300 mg dose has no added benefit and could have worse risks, than the 300/100 mg.
Due to the myriad of risks associated with self-administration, potential abuse and misuse, and accidental pediatric exposure, we agree with the FDA and the sponsor that, if this product is approved, it should only be administered by a healthcare provider in a clinical setting. This is the only way it has been studied, and there are no data on take-home use or self-administration of the product by patients. There are also no data on potentially dangerous effects of IV injection of this drug.
We commend the FDA for considering REMS (Risk Evaluation and Mitigation Strategy) that limit dispensing of this drug to settings that have a DATA-waived (Drug Addiction and Treatment Act 2000) prescriber or are DEA registrants. We agree that healthcare settings should be required to become certified to dispense this drug. We are not worried that it will unduly limit access; we are more worried that addicted persons will find ways around any safeguards, as they so often do.
In conclusion, to reduce deaths and addiction due to opioids, we must demand more from everyone. Prescribers must be better informed, REMS and ETASU (Elements to Assure Safe Use) must be sufficiently stringent, and scientific methods used to assess treatments must be sound. Given serious risks and concerns outweigh this drug’s minimal benefits, we cannot recommend approval of this drug based on current data.
Thank you for the opportunity to share our perspective.
The Psychopharmacologic Drugs Advisory Committee (PDAC) and the Drug Safety and Risk Management (DSaRM) Joint Committees voted 18-1, with 0 abstentions, in favor of approval of RBP:6000. Read more about the meeting here.