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 the Director of Public Health Policy Initiatives 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. We do not accept funding from the drug or medical device industry and I have no conflicts of interest.
We strongly support access to safe and effective treatments for opioid dependence. In 2014, more Americans died of opioid overdose than any other year on record so we need safe and effective treatment options. Currently available medications for opioid dependence are effective but could be improved to make them more difficult to divert and abuse and less likely to be accidentally ingested by small children. A long-acting medication could help improve adherence with therapy, potentially improving treatment success. However, in seeking to solve these problems, we must be certain we are not creating new problems.
- First, we do not have substantial evidence of probuphine’s efficacy, as required by statute. In fact, the evidence for efficacy for the population studied comes from a single controlled trial with multiple design flaws. For example:
- Patients requiring a significant amount of supplemental SL buprenorphine after the first month should be considered treatment non-responders due to the non-titratable nature of the implant. However, the study sponsor did not consider these patients as non-responders.
- Patients who received study drug but discontinued the study without providing any efficacy data were not included in the sponsor’s intention to treat analysis. Appropriate statistical analysis requires that these patients are included in the intention to treat population.
- Some missing urine toxicology tests were counted as negative tests. However, it is well-known that opioid-dependent patients often skip urine tests to avoid a positive test. Missing tests should be counted as positive.
If all of these uncertainties are accounted for, we no longer have convincing evidence of probuphine’s efficacy.
- Second, we also do not have substantial evidence of probuphine’s safety, as required by statute.
- Because the transition was not properly studied, we don’t have the information needed to instruct providers and patients on how to safely manage the transition period. It takes 3-4 weeks for the implant’s drug levels to stabilize when placed and many patients continue to require oral buprenorphine in addition to the implant.[1] The lack of information regarding how to safely transition patients from oral buprenorphine to the implant increases the risk that patients will suffer a dangerous relapse during this critical window. The risks of a poorly managed transition cannot be overstated since a relapse for patients who were previously stable would be particularly devastating. This is an unacceptable risk for stable patients.
- Many patients and physicians will think they can place the implant and forget it but the study found that many patients require supplemental oral doses to prevent relapse. In fact, the implant group used twice as many supplemental oral doses as the comparison group. This indicates that patients with the implant may be more at risk of being inadequately treated with the implant alone.
- Lastly, 84% of the patients studied were white and very few were studied beyond six months. This is not the real world of opioid addiction. Many of these patients will require treatment for years. We need long-term safety data from diverse populations. Patients will require a new incision every six months, creating an ongoing risk of harm due to bleeding and infectious complications. The probuphine implant has a higher risk for bleeding, complicated removal, and infection compared to contraceptive implants so we need a better understanding of its long-term safety profile.
In conclusion, based on the data presented and discussed today, I am disappointed to conclude that the risk-benefit profile of probuphine does not support its approval for the population studied.
Thank you for the opportunity to comment today and for consideration of our views.
For more information, see Dr. Rupp’s interviews in Maine Public Radio, The Daily Beast, and Inside Health Policy.
- This section of Dr. Rupp’s statement has been reworded here to clarify that the problem is the transition to stable therapeutic levels. As stated at the FDA meeting and in this written version, patients are vulnerable to relapse during that time.