In addition, monitoring for suicidal ideation and attempts was stepped up during the course of the clinical trials. Brodalumab’s sponsor, Valeant Pharmaceuticals, noted that the rates of suicidal ideation and attempts increased after implementation of the C-SSRS, while other neuropsychiatric symptoms remained stable or declined during the course of the studies. “This makes us think this is ascertainment bias,” said Valeant consultant Lauren Marangell, M.D., a psychiatrist and president of Brain Health Consultants.
Dr. Marangell also reported that, after stratification for preexisting psychiatric comorbidities and risk factors, “there is no question that the rate of SIB is higher in both arms with patients with baseline risk factors.” The FDA’s data analysis showed an 18-fold increase in the rate of SIB for brodalumab arm participants with a prior history of suicidality.
During its presentation, Valeant also pointed out that patients with histories of drug and alcohol abuse, depression, and suicidality were not specifically excluded from the clinical trials. This differentiates the brodalumab program from other biologic studies, “making the studies more characteristic of the real world,” said R.K. Pillai, Ph.D., Valeant vice president.
Dr. Levin’s analysis, one of several independent analyses conducted by different FDA divisions, found that the data were inconclusive. “We currently can’t conclude whether or not these are drug-related risks,” he said. Considering the critical severity of suicide as an outcome, “we must consider the application and regulatory actions carefully.”
Jean Kim, M.D., medical officer in CDER’s division of psychiatry products (DPP), noted that the number of suicides seen in the brodalumab trials “is higher than typically seen in DPP’s large psychiatric drug trials, which involve populations with higher psychiatric morbidity than patients with psoriasis.”
Patients with psoriasis are also known to have a baseline elevated risk of cardiovascular disease, and no committee member felt the brodalumab data showed any additional signal for major adverse cardiovascular events (MACEs) beyond what would be suspected in this population. “I don’t right now see a safety signal for MACE,” said panelist Michael Blaha, M.D., a cardiologist and director of clinical research at Johns Hopkins Ciccarone Center for Prevention of Heart Disease, Baltimore. He noted, however, that research is ongoing to elucidate the relationship between cytokine levels and MACE. “This question about whether cytokines raise or reduce rates for [cardiovascular] events is an open one.”
One of the dermatologists on the committee, Lynn Drake, M.D., said that her decision making was influenced by the disease burden psoriasis inflicts on the patients she sees in her daily practice. “These patients are ill. People tend to think it’s just skin disease. It is not just skin disease. … I’d hate to see our patients deprived of a drug that might help alleviate their symptoms,” said Dr. Drake.
Though committee members voiced some disagreement about whether a patient registry should be established, and if it should be voluntary, they were in agreement that patients and prescribers both be aware of the potential risks of brodalumab, without making any risk management strategy so burdensome that appropriate patients would be deterred from considering the medication. Psoriasis, Dr. Drake said, “is a devastating disease. We need this in our armamentarium.”
The proposed dosing for brodalumab is 210 mg injected subcutaneously weekly for 3 weeks, followed by 210 mg every 2 weeks thereafter.
The FDA usually follows the recommendations of its advisory committees. The panelists had no relevant financial disclosures.