Vanda Therapeutics receives a second FDA Complete Response Letter for HETLIOZ in jet lag disorder following a court-mandated re-review, after a federal appeals court set aside the FDA’s earlier rejection.
Written By: Pharmacally Medical News Desk
Vanda Pharmaceuticals has received a Complete Response Letter (CRL) from the U.S. Food and Drug Administration for the supplemental New Drug Application (sNDA) seeking approval of HETLIOZ for the treatment of jet lag disorder. The decision was issued by the U.S. Food and Drug Administration Center for Drug Evaluation and Research (CDER) on January 7, 2026, following an expedited re-review conducted under a collaborative framework agreement between the agency and the company.
FDA’s rationale for the CRL
While the FDA acknowledged positive efficacy signals from Vanda’s controlled clinical trials, the agency concluded that the submitted data did not meet the statutory standard for “substantial evidence of effectiveness” for jet lag disorder. The FDA’s primary concern centered on the study design, noting that the phase advance protocols used in the trials, involving 5-hour and 8-hour bedtime shifts, were not considered sufficiently representative of real-world jet travel. According to the agency, actual long-distance travel introduces additional factors such as cabin pressure changes, noise, lighting variations, and physical constraints that were not captured in the simulated models.
Vanda’s position on clinical evidence
Vanda has publicly disagreed with the FDA’s interpretation, emphasizing that phase advance models are widely accepted in circadian rhythm research as valid surrogates for eastward jet lag, which is driven primarily by circadian misalignment. The company argues that these models reliably reproduce the core biological disruption underlying jet lag without confounding variables unrelated to the disorder itself. Vanda highlighted convergent evidence from both simulated and actual transatlantic travel studies, showing improvements in sleep duration, time to persistent sleep, and next-day alertness with tasimelteon treatment.
Safety profile and regulatory history
The safety profile of HETLIOZ is well established, supported by more than a decade of post-marketing experience in its approved indications. Adverse events reported across studies have been predominantly mild. HETLIOZ is currently approved in the United States for Non-24-Hour Sleep-Wake Disorder and for nighttime sleep disturbances associated with Smith-Magenis syndrome. Vanda maintains that the totality of evidence submitted in the sNDA demonstrates clinically meaningful benefit on relevant sleep-focused endpoints for jet lag disorder.
Procedural background and next steps
This Complete Response Letter comes after an unusual regulatory path. In August 2025, the U.S. Court of Appeals for the D.C. Circuit reviewed an earlier FDA decision that had refused approval of HETLIOZ for jet lag disorder. The court did not rule on whether the drug should be approved. Instead, it found that the U.S. Food and Drug Administration had not adequately explained its rejection, despite statistically significant clinical results submitted by Vanda Pharmaceuticals. The court set aside the FDA’s prior refusal and directed the agency to take a fresh and more substantive look at the evidence. Following this ruling, Vanda and the FDA entered a collaborative framework agreement in October 2025, under which the FDA agreed to conduct an expedited re-review of the sNDA, including evaluation of narrower, sleep-focused indications.
Despite expressing appreciation for the FDA’s engagement, Vanda stated that the current decision does not fully reflect the court’s guidance or the collaborative intent of the re-review process. The company indicated it will continue to work constructively with the FDA while pursuing all appropriate regulatory and legal avenues to advance approval of HETLIOZ for jet lag disorder and broaden access to the therapy for travelers.
References
Vanda Pharmaceuticals Announces Receipt of FDA Decision Letter on HETLIOZ® Supplemental New Drug Application for Jet Lag Disorder, 08 January 2026, Vanda Pharmaceuticals Announces Receipt of FDA Decision Letter on HETLIOZ® Supplemental New Drug Application for Jet Lag Disorder
In a Major Win for Vanda, a Federal Appeals Court Overturns FDA’s Order Denying Approval of Hetlioz for the Treatment of Jet Lag Disorder, 18 August 2025, https://vandapharmaceuticalsinc.gcs-web.com/node/16556/pdf
Vanda Pharmaceuticals FDA Update for HETLIOZ® in the Treatment of Jet Lag Disorder, 19 August 2019, https://vandapharmaceuticalsinc.gcs-web.com/node/13696/pdf
United States of Appeal for the D. C. Circuit, On Petition for Review of an Order of the Food & Drug Administration, 15 August 2025, https://media.cadc.uscourts.gov/opinions/docs/2025/08/24-1049-2130249.pdf