Drugs

FDA Posts Biohaven Troriluzole Complete Response Letter

FDA has publicly released an 11/4 complete response letter issued to Biohaven on its NDA seeking approval of troriluzole to treat spinocerebellar ataxia (SCA). The quick posting comes just three days after the company received the rejection letter and thoroughly complained about the agency action in an 11/5 press release (see story). FDA’s letter concluded that the submission failed to demonstrate substantial evidence of effectiveness.

In the letter, the agency said that the company’s pivotal Study 206-RWE could not be considered “adequate and well-controlled” due to “design flaws and fundamental methodological limitations” that introduced multiple biases.

“After a comprehensive and detailed review of the submission, we have determined that substantial evidence of effectiveness has not been established,” FDA wrote, adding that the study’s reliance on external natural history data and its analytical methods failed to meet regulatory standards for drug approval.

The letter noted that Study 206-RWE used an externally controlled, real-world evidence (RWE) design comparing troriluzole-treated patients with natural history data from the Clinical Research Consortium for the Study of Cerebellar Ataxia (CRC-SCA). FDA reviewers found “limited comparability” between the two groups and said the propensity score matching failed to account for critical factors like baseline treatments, comorbidities, and geographic differences.

The agency also flagged “site overlap and expectation bias,” noting that 12 of the 18 CRC-SCA sites also participated in Biohaven’s Study 206 trial. FDA said this overlap created potential for selection bias and could have unconsciously influenced investigator assessments.

Additionally, the agency identified extensive missing data — with 52% of troriluzole subjects and 79% of control subjects lacking three-year functional outcome data — and said the absence was “not random,” undermining the reliability of results. When sensitivity analyses were applied to account for missing data, the apparent treatment benefit “became statistically non-significant,” according to the complete response letter.

FDA further cited inconsistencies in measurement methods, timing of assessments, and differences in outcome scoring systems between studies, which introduced additional uncertainty.

To move forward, FDA advised Biohaven to conduct a new adequate and well-controlled clinical trial showing a treatment effect on a clinically meaningful endpoint. The agency invited the company to meet with the division to discuss potential study designs to support a future NDA.

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