Tramadol gets rejected by FDA owing to safety concerns
USA: The US Food and Drug Administration (FDA) has issued a complete response letter ("CRL") regarding the New Drug Application ("NDA") for Avenue Therapeutics' IV tramadol. The CRL stated that although the pivotal Phase 3 clinical trials demonstrated statistically significant outcomes for all of the primary and many secondary endpoints, the FDA has determined that it cannot approve the application in its present form.
Intravenous (IV) tramadol is meant for the management of adults with moderate to moderately severe pain in a medically supervised healthcare setting.
The CRL stated that the NDA could not be approved in its current form because IV tramadol, which is intended to treat patients in acute pain who require an opioid, is not safe for the intended patient population. Specifically, if a patient requires an analgesic between the first dose of IV tramadol and the onset of analgesia, a rescue analgesic would be needed. The likely choice would be another opioid, which would result in opioid "stacking" and increase the likelihood of opioid-related adverse effects. Other than this potential safety concern, the FDA did not identify a safety signal in Avenue's clinical development program. In addition, the CRL stated that the FDA requires an adequate terminal sterilization validation prior to NDA approval, which is planned for later this quarter.
"We believe that our extensive clinical database strongly supports the value of treatment with IV tramadol as an effective alternative to intravenous Schedule II conventional opioids. We firmly stand behind the safety data in our NDA and the ultimate approvability of IV tramadol," said Lucy Lu, MD, President and Chief Executive Officer of Avenue Therapeutics. "We will request a meeting with the FDA as soon as possible and are committed to working closely with the agency to resolve these issues in order to bring this important medicine to patients and clinicians in the U.S."
The NDA for IV tramadol, which was submitted in December 2019, includes data from two phase 3 clinical trials involving patients who were treated following bunionectomy or abdominoplasty, along with an open-label safety study and an epidemiology study. Findings from the phase 3 trials showed that IV tramadol met all of the primary and most of the secondary endpoints.