Stephanie Fox-Rawlings, PhD, National Center for Health Research, February 12, 2019
Thank you for the opportunity to speak today on behalf of the National Center for Health Research. I am Dr. Stephanie Fox-Rawlings. 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 and medical device companies, so I have no conflicts of interest.
A drug that reduces symptoms of treatment-resistant depression within a few days could be valuable. Esketamine is particularly interesting because it works differently than other antidepressants on the market. Even if it was only practical or only effective for a few weeks or months, it could be beneficial. The data from the clinical trials for esketamine nasal spray are encouraging, but there are still important questions concerning its safety and efficacy.
Of greatest concern, only one of the three short-term, phase 3 efficacy studies had significant effects. This could mean that the positive result of this trial was due to chance or that the treatment is only effective for a narrow subset of patients or occur only under particular circumstances.
The randomized withdrawal trial suggests that the drug is effective, but the results are driven largely by one study site. And, since the drug can cause immediate side effects, it is likely that many patients in this study were not truly blinded. Eskatemine could have a role in treating treatment-resistant depression with it has short-term and or long-term effects, but these effects should be clearly demonstrated before FDA makes a decision about approval. If the drug is only effective for a definable subset of patients, the indication should specify those patients, because that would be important information for clinicians and patients.
There are several major safety concerns that need to be addressed.
The imbalance in deaths is of great concern. Six patients taking eskatamine died compared to zero patients taking placebo. Three deaths were due to suicide. Other antidepressant medications also can increase the risk for suicidal thoughts and behaviors. Esketamine works very differently than those other antidepresants, and if eskatamine increases the risk of suicide it is important to know if that increase is higher or lower compared to other antidepressants. Clinicians and patients need to know if the drug can increase this risk.
It is essential that patients receive the correct dose. The human factors study demonstrated that users were confused about the strength and dose of the product. This confusion increases the risk for avoidable, serious harm. If the drug is approved, it is very important that the company develop packaging and labeling to make sure that patients are given the proper dose. For that reason, a study demonstrating that the product can be used properly should be required before approval.
The applicant and FDA propose REMS to reduce the risk for patient harm due to adverse events and the risk for misuse or abuse. The proposed REMS, including education and certification for providers, patient education, in-clinic administration, and patient monitoring for at least 2 hours, could help keep patients safe, but only if they are actually carried out. These REMS should be required, not voluntary. If sites are lax in their training, dispensing, and monitoring practices, patients are likely to be harmed. REMS need to be carefully evaluated before widespread implementation and continually monitored to ensure that they are working.
Although we have strong concerns about this drug, it may be a better option for some patients than some other FDA-approved treatments for refractory depression, such as ECT.
In conclusion, esketamine has the potential to help patients, but please carefully consider the results of the clinical trials. There are still important efficacy and safety questions. New treatments need to have strong evidence that they work and can be used safely before approval. Another clinical trial, if it showed statistical and clinically meaningful results, would provide important information about dosage and appropriate patients.
The Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee voted in favor of approval (14 yes, 2 no, 1 abstain).