Did the FDA's 2025 letter ask Aldeyra for the same study as its 2023 letter?

Aldeyra Therapeutics Form 8-K, filed August 8, 2024

The dry eye chamber clinical trial was designed to satisfy the FDA’s New Drug Application (NDA) resubmission requirement, identified in the previously received complete response letter, of “at least one additional adequate and well-controlled study to demonstrate a positive effect on the treatment of ocular symptoms of dry eye.” Through the FDA Special Protocol Assessment process and additional comments, the FDA provided feedback on the clinical trial protocol and statistical plan.

Aldeyra Therapeutics Form 8-K, filed October 3, 2024

The resubmission includes previously disclosed positive results from a recently completed dry eye disease symptom trial requested by the FDA following review of the previously submitted NDA, as well as a draft label reflecting acute activity in reducing dry eye symptoms in a dry eye chamber trial, chronic activity in reducing dry eye symptoms in a field trial, and acute activity in reducing ocular redness in two dry eye chamber trials.

FDA Complete Response Letter, April 2, 2025 · page 2

Study 030 was similar in design to Study 024 from the original submission. When Study 030 is analyzed in a similar method to Study 024 from the initial submission (Visit 4 DEC score at each timepoint as the dependent variable), the study does not achieve statistical significance.

FDA Complete Response Letter, April 2, 2025 · page 2

You used Visit 2 and Visit 4 DEC results as the dependent variable and performed linear contrasts to obtain treatment differences between Visit 4 and Visit 2 results. The Agency finds the Study 030 primary efficacy endpoint analysis problematic, and we do not find the study results to be robust.

FDA Complete Response Letter, April 2, 2025 · page 2

You should conduct at least one additional adequate and well controlled study to demonstrate a positive effect on the treatment of ocular symptoms of dry eye. In the conduct of this study, you should not make changes to the protocol or the statistical analysis plan after the first subject is enrolled in the study without expressed agreement by the FDA.

Aldeyra Therapeutics Form 8-K, filed April 3, 2025

In November 2023, the FDA issued a Complete Response Letter to the initial NDA stating that at least one additional symptom trial was required. Following discussions with the FDA, and as part of a comprehensive strategy designed to account for disease heterogeneity and potential differences in clinical sites and environment, Aldeyra initiated three clinical trials assessing dry eye disease symptoms: a dry eye chamber trial, a clinical trial in a different dry eye chamber, and a six-week field trial.

Aldeyra Therapeutics Form 10-K, filed February 27, 2026

On November 27, 2023, Aldeyra announced that the FDA issued a Complete Response Letter (CRL) regarding the NDA submission. Although no safety or manufacturing issues with reproxalap were identified, the FDA stated in the letter that the NDA did not demonstrate “efficacy in treating ocular symptoms associated with dry eyes” and that “at least one additional adequate and well-controlled study to demonstrate a positive effect on the treatment of ocular symptoms of dry eye” should be conducted.

Aldeyra Therapeutics Form 8-K, filed September 29, 2026

Following an NDA submission and two NDA resubmissions of reproxalap for the treatment of dry eye disease, Aldeyra has received three Complete Response Letters, the first two of which recommended an additional clinical trial to “demonstrate a positive effect on the treatment of ocular symptoms of dry eye” and the most recent of which did not request further clinical trials but stated that the “totality of evidence from the completed clinical trials does not support the effectiveness of the product.” Over the course of the three NDA submissions, Aldeyra has provided data from nine adequate and well-controlled clinical trials, five of which achieved all multiplicity-controlled primary endpoints, consistent with or greater than the success rates of clinical trials conducted for approved dry eye disease products.