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    "disclaimer": "Do not rely on openFDA to make decisions regarding medical care. While we make every effort to ensure that data is accurate, you should assume all results are unvalidated. We may limit or otherwise restrict your access to the API in line with our Terms of Service.",
    "terms": "https://open.fda.gov/terms/",
    "license": "https://open.fda.gov/license/",
    "last_updated": "2026-08-13",
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  "results": [
    {
      "letter_date": "08/27/2025",
      "approver_title": null,
      "file_name": "CRL_NDA218679_20250827.pdf",
      "letter_year": "2025",
      "approval_status": "Unapproved",
      "approver_name": "Center for Drug Evaluation and Research",
      "approver_center": [],
      "company_rep": "Allison Lowry",
      "company_address": "1000 Holcomb Woods Parkway, Suite 270\nRoswell, GA 30076",
      "company_name": "Saol International Development Limited",
      "text": "ADMINISTRATION\n\ni Lk YN U.S. FOOD & DRUG\n\nNDA 218679\nCOMPLETE RESPONSE\n\nSaol International Development Limited\n% Saol Therapeutics Inc\n\nAttention: Allison Lowry\n\nHead of Regulatory\n\n1000 Holcomb Woods Parkway, Suite 270\nRoswell, GA 30076\n\nDear Allison Lowry:\n\nPlease refer to your new drug application (NDA) om\n\nfor sodium dichloroacetate.\n\nWe acknowledge receipt of your major amendment dated oe\n\nextended the goal date by three months.\n\n, Which\n\nWe have completed our review of this application, as amended, and have determined\nthat we cannot approve this application in its present form. We have described our\nreasons for this action below and, where possible, our recommendations to address\nthese issues.\n\nDEFICIENCY\n\nThe data presented in NDA 218679 failed to demonstrate substantial evidence of\neffectiveness for sodium dichloroacetate (DCA) for the treatment of pyruvate\ndehydrogenase complex deficiency (PDCD). We describe the rationale for this\nconclusion in further detail below.\n\nYou proposed to establish substantial evidence of effectiveness using two adequate\nand well-controlled trials: SL1009-01 and SL1009-02.\n\ne $SL1009-01, a randomized, double-blind, placebo-controlled trial, failed to\ndemonstrate a statistically significant benefit of DCA treatment on the\nprespecified primary analysis for the endpoint of change from baseline in ObsRO\nmotor in ITT population of PDCD subjects 10 months to 17 years of age\n(treatment difference 0.29 [95% Cl: -0.62, 1.21; p=0.52] favoring placebo arm).\nThe proposed post hoc analyses for the subgroup of subjects with Period 1\nbaseline ObsRO motor score = 8 were deemed inappropriate to determine the\npresence of a DCA treatment effect. The secondary endpoint of change from\nbaseline in plasma lactate produced estimated treatment differences that favor\n\nReference ID: 5650037\n\nNDA 218679\nPage 2\n\nDCA with a nominal two-sided p-value < 0.05. However, the changes in the\nbaseline plasma lactate were minimal and additional clinical and nonclinical data\nprovided did not support the observed reduction in plasma lactate as a surrogate\nendpoint that predicts clinical benefit in PDCD.\n\nSL1009-02 compared survival of subjects who received DCA in SL1009-01 to an\nexternal control derived from a published 2012 natural history study of PDCD by\nDeBrosse et al. The interpretability of the SL1009-02 survival analysis results is\nlimited by the following substantial differences between treated and control\ngroups identified during review and assessed in context of poorly defined natural\nhistory, significant clinical heterogeneity, and lack of reliable prognostic indicators\nfor PDCD:\n\na. Methods used to ascertain the age of disease onset were not clearly\ndefined in the protocol and statistical analysis plan for SL 1009-02; data\nfor the disease/symptom onset variable are incomplete, and imputation\nprotocol was inconsistently applied introducing bias against the external\ncontrol group.\n\nb. Observed differences in the presence of structural brain abnormalities\nmost commonly associated with severe disease favored the DCA-treated\n\ngroup.\n\nc. Differences in the methodologies used for diagnosis of PDCD to identify\nparticipants in the external control (i.e., enzyme activity) compared to\nthose who received DCA in SL1009-01 (i.e., genetic diagnosis via broad\nexome/genome sequencing) further limited between group comparability\nwith respect to PDCD severity favoring the DCA-treated group.\n\nd. Temporal bias: potential advances in medical care due to the temporal\nseparation (average 18 years) from the non-contemporaneous external\ncontrol favoring the DCA-treated group.\n\nTherefore, comparison between the DCA-treated group in SL1009-01 and the\nproposed external control cannot be used to assess the treatment effect of DCA\non survival and support claims of effectiveness.\n\nOverall, the data for two clinical trials you have provided in this application are\ninsufficient to establish substantial evidence of effectiveness of DCA for the treatment of\nPDCD.\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5650037\n\nNDA 218679\nPage 3\n\nINFORMATION NEEDED TO RESOLVE THE DEFICIENCY\n\nTo address this deficiency, submit the results of at least one new adequate and well-\ncontrolled trial demonstrating the effect of DCA on clinically meaningful endpoint(s) in\nthe intended population.\n\nIf you intend to demonstrate substantial evidence of effectiveness based on a single\nadequate and well controlled trial, you will also need to provide adequate confirmatory\nevidence substantiating the results of your adequate and well controlled trial.\n\nADDITIONAL APPROVABILITY ISSUES\n\nAs substantial evidence of effectiveness of DCA for the treatment of PDCD was not\nestablished in this application, we cannot conclude that the known and potential risks\nwith DCA in your application are outweighed by its benefit(s). Therefore, for the\npotential benefits and risks to be adequately evaluated, the following issues, including\nthose for premarketing risk assessment, and our recommendations for resolving those\nissues, must be addressed, in some manner, in the resubmission of your application.\n\nCompanion Diagnostic\n\n(b) (4)\n\nClinical Pharmacology\n\n2. You have not conducted a thorough QT/QTc study to evaluate the effect of DCA\non QT interval prolongation and the currently available clinical safety database in\nthe NDA is insufficient to assess the potential effect of DCA on the QT interval.\nConduct a thorough QT/QTc study to evaluate the effect of DCA on QT interval\nprolongation.\n\n3. You have not evaluated the effect of food on the pharmacokinetics (PK) of DCA.\nConduct a clinical trial to evaluate the effect of food on the PK of DCA.\n\nNonclinical\n(b) (4)\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5650037\n\nNDA 218679\nPage 4\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5650037\n\nNDA 218679\nPage 5\n\n(b) (4)\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\nThe review of your proposed proprietary name has been terminated due to the\ndeficiencies with the application as described in this letter. Please resubmit the\nproposed proprietary name when you respond to all of the application deficiencies that\nhave been identified in this letter. If you do not have a conditionally acceptable\nproprietary name, you may submit a Request for Proprietary Name Review to your IND.\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\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\n5 https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources\n\n6 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: 5650037\n\nNDA 218679\nPage 6\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\nmay consider your lack of response a request to withdraw the application under\n\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\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5650037\n\nNDA 218679\nPage 7\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\nIf you have any questions, contact\n\nSincerely,\n\n{See appended electronic signature page}\n\nCenter for Drug Evaluation and Research\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 5650037\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\n08/27/2025 03:31:21 PM\n\nReference ID: 5650037\n",
      "application_number": [
        "NDA 218679"
      ],
      "letter_type": "COMPLETE RESPONSE"
    }
  ]
}