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  "meta": {
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    "license": "https://open.fda.gov/license/",
    "last_updated": "2026-08-13",
    "results": {
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  "results": [
    {
      "letter_date": "11/04/2025",
      "approver_title": null,
      "file_name": "CRL_NDA210862_20251104.pdf",
      "letter_year": "2025",
      "approval_status": "Unapproved",
      "approver_name": "4)",
      "approver_center": [],
      "company_rep": "Marianne Frost, MA",
      "company_address": "215 Church Street\nNew Haven, CT 06510",
      "company_name": "Biohaven Therapeutics, Ltd.",
      "text": "ADMINISTRATION\n\n¢ Fy U.S. FOOD & DRUG\n\nNDA 210862\nCOMPLETE RESPONSE\n\nBiohaven Therapeutics, Ltd.\n\nc/o Biohaven Pharmaceuticals, Inc.\nAttention: Marianne Frost, MA\n\nSenior VP, Regulatory Affairs and Operations\n215 Church Street\n\nNew Haven, CT 06510\n\nDear Marianne Frost:\n\nPlease refer to your new drug application (NDA) om\n\n&) 4)\n\nfor (troriluzole) capsules.\n\nWe acknowledge receipt of your major amendments dated oe\n\n, which extended the goal date by three months.\nWe also acknowledge receipt of your amendment dated oe . The new\nnonclinical studies submitted in the amendment were not reviewed for this action. You\nmay incorporate applicable sections of the amendment by specific reference as part of\nyour response to the deficiencies cited in this letter.\n\nCLINICAL AND STATISTICAL\n\nThe Agency initially raised concerns with your proposal to conduct Study 206-RWE, an\nexternally controlled study comparing data from Study 206 to natural history controls at\na . We noted that such a study would likely be\ninadequate to provide substantial evidence of effectiveness, particularly with\nconsideration that Study 206, the randomized, double-blind, placebo-controlled study,\nfailed on all primary and secondary endpoints in the pre-specified analysis population.\nThe Agency noted that “the proposed natural history data source does not appear to be\nfit-for-purpose, and the externally controlled analyses will likely generate results that are\ndifficult to interpret and subject to biases due to the baseline differences between the\nstudy subjects and external control subjects”.\n\nAlthough the Agency provided feedback on the design of t the protocol and statistical\nanalysis plan for Study 206-RWE\n\n), we continued to express concerns that the post hoc, externally\ncontrolled study alone seemed inadequate to demonstrate substantial evidence of\neffectiveness because the study would not be blinded or prespecified, would include\npreviously analyzed data, and would be susceptible to residual confounding due to\nunmeasured differences in subjects from Study 206 compared to the natural history\n\nReference ID: 5689232\n\nNDA 210862\nPage 2\n\ncohorts. We also reiterated these concerns at the oe)\n\n, during which we stated that Study 206-RWE was not considered to be an\nadequate and well-controlled investigation, and therefore, it would not be capable of\nproviding the primary support for demonstration of substantial evidence of\neffectiveness.\n\nGiven the seriousness and rarity of spinocerebellar ataxia, the Agency determined that\nthe NDA should be filed to allow for thorough review of the data. After a\ncomprehensive and detailed review of the submission, we have determined that\nsubstantial evidence of effectiveness has not been established for troriluzole for the\ntreatment of spinocerebellar ataxia. A detailed discussion of the deficiencies follows.\n\n|. Study 206-RWE cannot be considered an adequate and well-controlled\ninvestigation, as defined in CFR 314.126, to support effectiveness due to\ndesign flaws and fundamental methodological limitations that have\nintroduced bias into the study.\n\n1. Limited comparability between trial subjects and external controls and\nresidual biases: Several factors undermined the reliability of the Clinical\nResearch Consortium for the Study of Cerebellar Ataxia natural history study\n(CRC-SCA) as a control arm in Study 206-RWE. The propensity score\nmatching could not address important factors that could affect disease\nprogression such as baseline supportive treatments, comorbidities, and\ngeographic factors, which were not measured and therefore could not be\nmatched. E-values as low as 1.1 to 1.3, indicate that even modest\nunmeasured confounding could eliminate statistical significance. Of note,\nwhen matching included 1-year progression rates to better control for\nbaseline disease trajectory differences, the treatment effect became\nstatistically nonsignificant at both Year 2 and Year 3 (p=0.3849 at Year 3),\nsuggesting that the observed benefits may be entirely attributable to baseline\ndifferences rather than true treatment effects. The comparison between\nprogression rates at 1 year in subjects randomized to placebo in Study 206\nand CRC-SCA controls revealed significant differences favoring placebo\n(particularly in SCA1 and SCA2 genotypes), providing direct evidence of\nconfounding that undermines confidence in CRC-SCA as a control arm and in\nthe results of Study 206-RWE.\n\n2. Site overlap, selection and expectations biases: Two-thirds of CRC-SCA\nnatural history sites (12 of 18) were also among the 21 U.S. sites that\nconducted Study 206. This overlap of study sites creates significant potential\nfor multiple biases. First, selection bias may occur because Study 206 had\nstrict eligibility criteria while CRC-SCA had minimal restrictions. At sites\nsimultaneously participating in both studies, we cannot rule out that Study 206\nscreening failures might be enrolled in the CRC-SCA population creating\npotential for systematic selection biases. Second, expectation bias likely\noccurred because the same unblinded investigators, examiners, and raters\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5689232\n\nNDA 210862\nPage 3\n\nassessed both populations with knowledge of study enrollment. This\nknowledge could unconsciously influence disease severity ratings. Although\nthe impact of these biases on the observed treatment effect of troriluzole\ncannot be reliably quantified, these biases add substantial uncertainty to the\nstudy results in addition to other unmeasured confounders.\n\n3. Substantial Missing Data: There was a substantial amount of missing data\nin Study 206-RWE, with 52% of troriluzole-treated subjects and 79% of\nCRC-SCA controls missing Year 3 functional Scale for the Assessment and\nRating of Ataxia (f-SARA) data for the primary efficacy analysis. Non-\ncompleters in the troriluzole group had significantly higher baseline disease\nseverity (worse f-SARA scores: 5.4 versus 4.7, p=0.0335). The Jump-to-\nReference (J2R) analysis, which assumes treatment benefits are lost when\nsubjects discontinue, and was a pre-specified sensitivity analysis, showed\nthe 3-year result became statistically non-significant (p=0.1023 instead of\np=0.0301). Therefore, the treatment effect observed on the primary analysis\nof Study 206-RWE is unreliable, because of the extremely large percentage\nof missing data, combined with evidence of informative censoring\n(missingness was not random), and lack of robustness under plausible\nmissing data assumptions.\n\n4. Systematic Timing Bias: Critical timing discrepancies existed between\nstudies, with CRC-SCA using 365-day periods compared to 336-day periods\nfor Study 206, resulting in CRC-SCA subjects being assessed progressively\nlater (up to 90 days at Year 3). When timing was properly aligned in sensitivity\nanalyses, the results failed to achieve nominal statistical significance,\n(p=0.0997), indicating that the 90-day timing difference in the assessment\nmay not fully explain the entire observed benefit but accounted for a\nstatistically meaningful portion of the effect.\n\n5. Measurement Methodology Differences: The primary outcome\nassessment differed fundamentally between the study populations in Study\n206 and CRC-SCA. Study 206 used direct f-SARA administration using the\nvalidated 16-point scale with standardized instructions and trained raters\nwhile CRC-SCA used the original 40-point SARA scale, and these scores\nwere subsequently mapped to f-SARA equivalents using a predetermined\nconversion algorithm. This mapping process introduced notable\nmeasurement differences, including increased variability in the mapped f-\nSARA gait subscores and overall f-SARA total scores compared to the\ndirectly measured f- SARA in the troriluzole group, suggesting that the\nstatistical assumptions of homogeneous variance-covariance structures\nacross the two studies underlying your primary MMRM efficacy analysis is\nnot appropriate.\n\n6. Lack of Pre-specification: The primary analysis of Study 206-RWE is based\non the comparison of Year 3 data from Study 206 (randomization phase and\nopen-label extension) to natural history controls from CRC-SCA. The protocol\n\nU.S. Food and Drug Administration\n\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5689232\n\nNDA 210862\nPage 4\n\nand statistical analysis plan (SAP) for Study 206-RWE were designed with\nknowledge of unblinded data of both Study 206 and the natural history data\nfrom CRC-SCA and EUROSCA, as well as with knowledge of prior analyses\ncomparing Study 206 with the natural history data. Specifically,\n\n, you presented results from\nan analysis of the 3-year OLE phase from Studies 206 and 201 compared to\nexternal controls from EUROSCA and CRC-SCA cohorts, using a matching-\nadjusted indirect comparison (MAIC) analysis. You have stated that the\nprotocol and statistical analysis plan for Study 206-RWE were “prespecified”,\nbased on the argument that the analysis included data on 21 subjects whose\nyear 3 data in the open-label extension of Study 206 had not yet been\nanalyzed at the time of the drafting of the protocol and SAP for Study 206-\nRWE. We do not agree that this constitutes “prespecification”.\n\nPrespecification of statistical methods prior to analyzing data is critical to\nreduce bias and maintain study integrity by ensuring that the choice of the\nstatistical analysis methods is not influenced by knowledge of the data. We\nacknowledge that Study 206-RWE uses analyses that are modified from\nthese prior MAIC analyses, including new data from 21 subjects, and added\nsupplemental analyses to evaluate potential biases. However, the SAP for\nStudy 206-RWE was drafted in 2024, with prior knowledge of the results of\nthe MAIC analyses presented to the Agency in 2023. In addition, the source\ndata used in Study 206-RWE and the prior MAIC analyses largely overlap,\nand the same outcome measure was evaluated at the same time points. This\nis not consistent with the FDA draft guidance for industry, Considerations for\nthe Design and Conduct of Externally Controlled Trials for Drug and Biological\nProducts (February 2023), that recommends finalizing study protocols and\nselecting external control arms before initiating externally controlled trials and\ngreatly affects the strength of evidence from the study because unconscious\nand conscious biases may be introduced.\n\nIt is our position that neither the design of Study 206-RWE nor the\nhypotheses underlying the SAP-specified analyses can be considered\n“prespecified” and that significant biases have influenced the study results.\n\nCollectively, these issues suggest the potential for significant biases in the\nestimation of efficacy of troriluzole that cannot be reliably quantified or corrected.\nThe treatment difference of -0.79 observed on the f-SARA at Year 3 (p=0.0301)\nbetween the troriluzole-treated group and the CRC-SCA cohort is of uncertain\nclinical meaningfulness. The treatment effect is not sufficiently large or robust to\novercome the concerns with the multiple methodological limitations identified\nabove. Therefore, 206-RWE is unable to serve as an adequate and well-controlled\nstudy that can contribute to substantial evidence of effectiveness.\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5689232\n\nNDA 210862\n\nPage 5\n\nIl. | Methodological issues preclude the ability to use the secondary efficacy\nanalyses of Study 206-RWE and post hoc analyses of Study 206 as\nconfirmatory evidence.\n\nAlthough the ability to use confirmatory evidence depends first on the presence\nof a single adequate and well-controlled study, which you do not have, we also\nreviewed the data that you proposed as confirmatory evidence.\n\n1.\n\nSecondary efficacy analyses of Study 206-RWE: These analyses suffer\nfrom the same fundamental limitations as the primary efficacy analysis.\nThe treatment effect observed in the troriluzole-treated group compared to\nthe CRC-SCA cohort, at Year 2 and Year 1, is smaller than the effect\nobserved at Year 3 and insufficient to overcome the multiple\nmethodological limitations as described in Section I.\n\nAdditionally, the European Integrated Project on Spinocerebellar Ataxias\n(EUROSCA) demonstrated significantly faster disease progression rates\ncompared to North American populations. This combined with limited\nbaseline data availability, which prevents adequate adjustments and\nassessments, renders EUROSCA, either alone or in combination with the\nCRC-SCA, inadequate as an external control.\n\nPost hoc SCA genotype 3 subgroup analyses of Study 206: Study 206\nfailed to achieve statistical significance on its prespecified primary endpoint\nof the f-SARA at 48 weeks. Post hoc subgroup analyses in the SCA\ngenotype 3 population were not prespecified. When accounting for multiple\ncomparisons and applying the prespecified covariates to the statistical\nmodel, the results were not statistically or clinically persuasive.\n\nFall Risk Analysis of Study 206: Your analysis of fall risk reduction based\non adverse event reporting does not support effectiveness. The analysis\nwas not prespecified. Moreover, the data suffers from multiple significant\nlimitations. Inspections identified systematic under-reporting of adverse\nevents and incorrect coding of fall events in the original adverse event\ndataset. It was also identified that investigators were instructed to only\nrecord falls that resulted in injury which likely led to underreporting of falls.\nWhen using the corrected dataset with an appropriate statistical model\n(which may still not capture all falls that occurred), the difference in relative\ntisk reduction between troriluzole-treated subjects and controls did not\nachieve nominal statistical significance.\n\nIn order to address these deficiencies, you will need to provide data from an adequate\nand well-controlled study that demonstrates an effect on a clinically meaningful\nendpoint in order to establish the effectiveness of troriluzole for the treatment of\nspinocerebellar ataxia. We recommend that you meet with the Division to discuss the\nevidence that will be needed to support a future NDA for the treatment of SCA with\n\ntroriluzole.\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5689232\n\nNDA 210862\nPage 6\n\nNONCLINICAL\n\n(b) (4)\n\nADDITIONAL COMMENTS:\nWe have the following comments/recommendations that are not approvability issues:\n\nReassess and propose the dosage modifications for relevant intrinsic and\nextrinsic factors.\n\nPRESCRIBING INFORMATION\n\nWe reserve comment on the proposed labeling until the application is otherwise\nadequate. We encourage you to review the labeling review resources on the\nPrescription Drug Labeling Resources! and Pregnancy and Lactation Labeling Final\nRule? websites, including regulations and related guidance documents and the Selected\nRequirements for Prescribing Information (SRPI) - a checklist of important format items\nfrom labeling regulations and guidances.\n\nCARTON AND CONTAINER LABELING\n\nWe reserve comment on the proposed labeling until the application is otherwise\nadequate.\n\nPROPRIETARY NAME\n\nPlease refer to our correspondence dated, oe , which addresses the\nproposed proprietary name,! ™ This name was found conditionally acceptable\npending approval of the application in the current review cycle. Please resubmit the\nproposed proprietary name when you respond to all of the application deficiencies that\nhave been identified in this letter.\n\nSAFETY UPDATE\n\nWhen you respond to the above deficiencies, include a safety update as described at\n21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical\n\n1 https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources\n\n2 https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs-\nfinal-rule\n\nU.S. Food and Drug Administration\n\nSilver Spring, MD 20993\n\nwww.fda.gov\n\nReference ID: 5689232\n\nNDA 210862\nPage 7\n\nand clinical studies/trials of the drug under consideration regardless of indication,\ndosage form, or dose level.\n\n(1) Describe in detail any significant changes or findings in the safety profile.\n\n(2) When assembling the sections describing discontinuations due to adverse\nevents, serious adverse events, and common adverse events, incorporate new\nsafety data as follows:\n\ne Present new safety data from the studies/clinical trials for the proposed\nindication using the same format as in the original submission.\n\ne Present tabulations of the new safety data combined with the original\napplication data.\n\ne Include tables that compare frequencies of adverse events in the original\napplication with the retabulated frequencies described in the bullet above.\n\ne For indications other than the proposed indication, provide separate tables for\nthe frequencies of adverse events occurring in Clinical trials.\n\n(3) Present a retabulation of the reasons for premature trial discontinuation by\nincorporating the drop-outs from the newly completed trials. Describe any new\ntrends or patterns identified.\n\n(4) Provide case report forms and narrative summaries for each subject who died\nduring a Clinical trial or who did not complete a trial because of an adverse event.\nIn addition, provide narrative summaries for serious adverse events.\n\n(5) Describe any information that suggests a substantial change in the incidence of\ncommon, but less serious, adverse events between the new data and the original\napplication data.\n\n(6) Provide updated exposure information for the clinical studies/trials (e.g., number\nof subjects, person time).\n\n(7) Provide a summary of worldwide experience on the safety of this drug. Include\nan updated estimate of use for drug marketed in other countries.\n\n(8) Provide English translations of current approved foreign labeling not previously\nsubmitted.\n\nOTHER\n\nWithin one year after the date of this letter, you are required to resubmit or take other\nactions available under 21 CFR 314.110. If you do not take one of these actions, we\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5689232\n\nNDA 210862\nPage 8\n\nmay consider your lack of response a request to withdraw the application under\n21 CFR 314.65. You may also request an extension of time in which to resubmit the\napplication.\n\nA resubmission must fully address all the deficiencies listed in this letter and should be\nclearly marked with \"RESUBMISSION\" in large font, bolded type at the beginning of the\ncover letter of the submission. The cover letter should clearly state that you consider\nthis resubmission a complete response to the deficiencies outlined in this letter. A partial\nresponse to this letter will not be processed as a resubmission and will not start a new\nreview cycle.\n\nYou may request a meeting or teleconference with us to discuss what steps you need to\ntake before the application may be approved. If you wish to have such a meeting,\nsubmit your meeting request as described in the draft guidance for industry Formal\nMeetings Between the FDA and Sponsors or Applicants of PDUFA Products.\n\nThe product may not be legally marketed until you have been notified in writing that this\napplication is approved.\n\nIf you have any questions, contact oe\n\nSincerely,\n\n{See appended electronic signature page}\n4)\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5689232\n\nSignature Page 1 of 1\n\nThis is a representation of an electronic record that was signed\nelectronically. Following this are manifestations of any and all\nelectronic signatures for this electronic record.\n\n(b) (4)\n\n11/04/2025 10:20:43 AM\n\nReference ID: 5689232\n",
      "application_number": [
        "NDA 210862"
      ],
      "letter_type": "COMPLETE RESPONSE"
    }
  ]
}