On February 1, 2019, the FDA approved Evolus, Inc.’s Jeuveau™ (prabotulinumtoxinA-xvfs), “for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients.” Key findings from the FDA’s Multi-Discipline Review and Other Review(s) are summarized below.
Efficacy was demonstrated in two pivotal clinical trials (EV-001 and EV-002). The Phase 3 clinical trials were double-blind and randomized (n=330 and 324, respectively). These two trials provide the primary supporting evidence for the safety and effectiveness of JEUVEAU.
The relatively low risk profile for Jeuveau for the treatment of glabellar lines is supported by the safety data in the two U.S. clinical trials (EV-001 and EV-002), the EU clinical trial (EV-003), and the long-term open-label studies (EV-004 and EV-006). In all, 1,659 received treatment with Jeaveau, 246 with BOTOX® (only in EV-003), and 211 received treatment with Placebo.
The applicant also included real-world data in its submission —
Purpose: The safety considerations are recommended by the Agency’s draft guidance document, entitled “Guidance for Industry. Upper Facial Lines: Developing Botulinum Toxin Drug Products,” which recommends excluding pregnant subjects and nursing mothers from trials of botulinum drug products for the temporary treatment of upper facial lines.”
What was done: The Applicant searched the medical literature to identify articles related to botulinum drug products and pregnancy. Multiple articles were identified, including an article summarizing the pregnancy outcomes from Allergan’s Allergan Global Safety Database (1990 to 2013).* The authors identified 232 pregnancies of maternal BOTOX exposure with known outcomes.
Outcome: The prevalence rate of overall fetal defects was 2.7%, similar to background rates in the general population. However, due to limitations of the study, the Division of Epidemiology (DEPI) recommended providing, in the product label, a qualitative summary of the postmarket requirements along with a statement about the unknown causal relationship between BOTOX exposure and fetal loss and abnormal birth outcomes.
DEPI’s articulation of the limitations of the study:
- The data are collected as part of Allergan’s adverse event reporting system so it more closely resembles FDA Adverse Event Reporting System (FAERS) data than more rigorous observational study designs.
- Since the data are essentially a case series, the analysis does not give any information on risk.
- In addition to the type of data, major limitations of the study include the potential reporting bias and missing data on (or lack of) complete medical information.
*Brin MF, Kirby RS, Slavotinek A, Miller-Messana MA, Parker L, Yushmanova I, Yang H. Pregnancy outcomes following exposure to onabotulinumtoxinA. Pharmacoepidemiol Drug Saf. 2016 Feb;25(2):179- 87.