SUMMARY  

• A total of 9 deaths were reported in the SPRAVATO clinical trial program for treatment-resistant depression (TRD) (including in an ongoing phase 3, open-label, safety extension study) and the clinical trial program for major depressive disorder (MDD) in patients with active suicidal ideation and intent.^1-3  Study investigators assessed these deaths as either unrelated or doubtfully related to SPRAVATO.
  • Four of the deaths that occurred in the TRD development program were due to cardiovascular events or physical trauma resulting from accidents.^{1, 2} One death was due to COVID-19-related pneumonia.⁴
  • Three deaths in the SPRAVATO TRD development program were completed suicides, all occurring during open-label treatment. The suicide completion rate (0.49 per 100 patient-years of treatment) was comparable to the background rate of 0.47 (95% CI: 0.22–1.00) completed suicides per 100 patient-years reported in a meta-analysis of patients with TRD.^{5, 6} After extensive review by study site investigators, none of the suicides were deemed related to SPRAVATO.
  • Adeath due to a completed suicide was reported in a patient previously treated with SPRAVATO in the follow-up phase of a trial in patients with MDD with active suicidal ideation and intent.³
• In postmarketing safety data from the SPRAVATO Risk Evaluation and Mitigation Strategy (REMS) and the SPRAVATO global medical safety databases from 5 March 2019 to 5 January 2023, 147 deaths were reported, of which 47 were completed suicides.⁷
• In another analysis of postmarketing safety data (March 2019 to first quarter 2020) using the Food and Drug Administration Adverse Event Reporting System (FAERS), 22 deaths were identified, of which half were completed suicides.⁸

CLINICAL trial DATA

In the 6 completed Phase 2 and 3 TRD studies, 4 deaths were reported in 1,708 subjects receiving SPRAVATO (611 patient-years of exposure⁶; 1 during double-blind treatment and 3 during open-label treatment).⁹ No deaths were reported in these studies among the 486 subjects who received oral AD + placebo (108 patient-years of exposure). In an ongoing long-term, open-label safety extension study (SUSTAIN-3), 4 deaths were reported in SPRAVATO-treated subjects.^{1, 4, 9} Of the 452 patients in the clinical program for MDD in patients with active suicidal ideation and intent, 1 death was reported in a patient previously treated with SPRAVATO during the follow-up phase.³ Additional details can be found in the Table: Serious Adverse Events of Death.

Although death by suicide is always tragic, in the SPRAVATO TRD development program, the suicide completion rate (0.49 per 100 patient-years of treatment) was comparable to the background rate of 0.47 (95% CI: 0.22–1.00) completed suicides per 100 patient-years reported in a different study in a TRD population.^{5, 6}  After extensive review by study site investigators, none of the suicides were deemed related to SPRAVATO. Additionally, safety data was reviewed every 6 months by an Independent Data Monitoring Committee (IDMC) to ensure the continuing safety of the patients enrolled in the phase 3 trials.^{10, 11}

Table: Serious Adverse Events of Death presents additional details regarding the deaths.¹

postmarketing safety data

REMS Database

Safety data of interest were gathered from REMS patient monitoring forms completed by certified US healthcare settings and pharmacies and a separate SPRAVATO global medical safety database (which includes AEs reported from the REMS and other sources) from 5 March 2019 to 5 January 2023.⁷ There were a total of 147 cases reporting 160 fatal events. Of the 147 cases, 136 reported only 1 fatal event which included 67 deaths not otherwise specified, 45 completed suicide, 3 overdose, 2 COVID-19 infection, 2 road traffic accidents and 1 death each due aortic aneurysm, arteriosclerosis, Candida infection, cerebrovascular accident, diabetes mellitus, drug abuse, electrolyte imbalance, failure to thrive, hepatic cirrhosis, intestinal obstruction, intestinal perforation, multimorbidity, myocardial infarction, neoplasm malignant, post procedural complication, pulmonary embolism, and sepsis. Eleven remaining fatal cases which reported more than 1 fatal event: Cardiac disorder, sepsis, and COVID-19; cardiovascular disorder, multiple organ dysfunction syndrome, and cerebrovascular accident; toxicity to various agents and accidental overdose; hip fracture and gall; hallucination auditory and completed suicide; pneumonia and multiple organ dysfunction syndrome; toxicity to various agents and completed suicide; suspected suicide and alcohol use; overdose and brain injury; organ failure and COVID-19; and substance abuse and accidental overdose. The majority of deaths were assessed by Global Medical Safety as not related to SPRAVATO treatment.⁷

FDA Adverse Event Reporting System (FAERS)

An analysis was conducted using the FAERS to identify relevant safety signals for SPRAVATO.⁸ A case/non-case study design was utilized in which cases were defined by reports about SPRAVATO, while non-cases were represented by AEs recorded for all other drugs in FAERS over the first year of SPRAVATO approval. If the proportion of AEs of interest was greater in cases versus non-cases, then this was considered a disproportionality signal. AEs were classified into four categories, according to their predictability: expected AEs with a detected signal, expected AEs without a signal, disease-related AEs, or unexpected AEs.

There was a total of 2,274 SPRAVATO-related AEs in 962 patients with 389 serious AEs, including 22 deaths. The causes of death involved completed suicide (n=11); death not specified (n=4); road traffic accident (n=2); pulmonary embolism, myocardial infarction, multimorbidity, intestinal perforation, and electrolyte imbalance/decreased blood glucose (1 each). The authors noted that the results must be interpreted with caution, partly due to the FAERS database having limitations, including the inability to infer causality, barriers to reporting, limitations in the quality of information received, and the inability to calculate an incidence rate due to a lack of a denominator.⁸ Furthermore, the FAERS does not include information on the patients’ baseline suicidality and illness severity (which are important risk factors for suicide-related AEs).¹⁵

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, DERWENT Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 12 May 2023.