{
  "meta": {
    "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",
    "results": {
      "skip": 0,
      "limit": 1,
      "total": 1
    }
  },
  "results": [
    {
      "letter_date": "10/08/2024",
      "approver_title": "Reference ID: 5459701",
      "file_name": "CRL_NDA217724_20241008.pdf",
      "letter_year": "2024",
      "approval_status": "Unapproved",
      "approver_name": "Center for Drug Evaluation and Research",
      "approver_center": [],
      "company_rep": "Christopher R. DeFusco, PhD",
      "company_address": "50 Milk Street, 16\" Floor\nBoston, MA 02109",
      "company_name": "Zealand Pharma US, Inc.",
      "text": "ADMINISTRATION\n\no FN U.S. FOOD & DRUG\n&\n\nNDA 217724/Original 1\nCOMPLETE RESPONSE\n\nZealand Pharma US, Inc.\n\nAttention: Christopher R. DeFusco, PhD\nHead of US Regulatory Affairs\n\n50 Milk Street, 16\" Floor\n\nBoston, MA 02109\n\nDear Dr. DeFusco:\n\nPlease refer to your new drug application oe\n\nor dasiglucagon injection.\n\n() 4)\n\nWe acknowledge receipt of your amendment dated which constituted a\n\ncomplete response to our action letter.\n\nNDA 217724 provides for the use of dasiglucagon injection for the following indications\nwhich, for administrative purposes, we have designated as follows:\n\n(b) (4)\n\nThe subject of this action letter is NDA 217724/Original 1. oe\n\nAll future submissions to NDA 217724/Original 1 and NDA 217724/Original 2 should\nspecify the NDA number and the Original number to which each submission pertains.\n\nWe have completed our review of NDA 217724/Original 1 and have determined that we\ncannot approve this application in its present form. We have described our reasons for\nthis action below and, where possible, our recommendations to address these issues.\nFACILITY INSPECTIONS\n\n(b) (4)\n\nFollowing a current good manufacturing practice (CGMP) inspection of\n\nlisted in this application, FDA conveyed deficiencies to the\nrepresentative of the facility. The facility should provide satisfactory responses to these\n\nReference ID: 5459701\n\nNDA 217724/Original 1\nPage 2\n\ndeficiencies to the FDA office indicated on the FDA 483 prior to your complete\nresponse. The facility's satisfactory responses are dependent on FDA’s determination\nhat the facility has come into compliance with CGMP and may require re-inspection of\nhe facility. The deficiencies identified during the inspection may not be specific to your\npending application, therefore, you should coordinate with the facility for timely\nresolution. Your complete response should include the date(s) of the facility's\nresponse(s) to the FDA Form 483. Please refer to Compliance Program CP 7356.002\n‘or guidance on post inspection activities. Following resolution of the CGMP inspection,\nFDA may need to conduct a pre-approval inspection (PAI) of the facility. Satisfactory\noutcomes of both the PAI and the CGMP surveillance inspections will be needed prior\n\n‘0 an approval of the application. As the Applicant, we do not expect a response to this\nacility related deficiency when responding to any other deficiencies cited in this or other\nletters, instead, please work with the facility, as applicable, in resolving the related\ndeficiencies.\n\nPRESCRIBING INFORMATION\n\nSubmit draft labeling that is responsive to our electronic communication dated\n\nPrior to resubmitting the labeling, use the Selected Requirement of Prescribing\nInformation (SRPI) checklist to correct any formatting errors to ensure conformance with\nthe format items in regulations and guidances. In addition, submit updated content of\nlabeling [21 CFR 314.50(I)(1)(i)] in structured product labeling (SPL) format as\ndescribed at FDA.gov.'\n\nTo facilitate review of your submission, provide a highlighted or marked-up copy that\nshows all changes, as well as a clean Word version. The marked-up copy should\ninclude annotations that support any proposed changes.\n\nYour proposed Prescribing Information (PI) must conform to the content and format\nregulations found at 21 CFR 201.56(a) and (d) and 201.57. As you develop your\nproposed PI, we encourage you to review the labeling review resources on the\nPrescription Drug Labeling Resources? and Pregnancy and Lactation Labeling Final\nRule? websites, which include:\n\ne The Final Rule (Physician Labeling Rule) on the content and format of the PI for\nhuman drug and biological products\n\n1 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm\n\n2 https://www.fda.gov/drugs/laws-acts-and-rules/prescription-drug-labeling-resources\n\n3 https://www.fda.gov/drugs/labeling-information-drug-products/pregnancy-and-lactation-labeling-drugs-\nfinal-rule\n\nReference ID: 5459701\n\nNDA 217724/Original 1\nPage 3\n\nThe Final Rule (Pregnancy and Lactation Labeling Rule) on the content and\nformat of information in the PI on pregnancy, lactation, and females and males of\nreproductive potential\n\ne Regulations and related guidance documents\n\ne Asample tool illustrating the format for Highlights and Contents, and\n\ne The SRPI - a checklist of important format items from labeling regulations\nand guidances.\n\ne FDA's established pharmacologic class (EPC) text phrases for inclusion in the\nHighlights Indications and Usage heading.\n\ne Additional resources for the PI, patient labeling, and carton/container labeling.\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 the application deficiencies.\n\nSAFETY UPDATE\n\nWhen you respond to the above deficiencies, include a safety update as described in\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 events\n\nReference ID: 5459701\n\n(AE), serious adverse events (SAE), and common AEs, incorporate new safety\ndata as follows:\n\ne Present new safety data from the studies/clinical trials for the proposed\nindication using the same format as the original NDA submission.\n\ne Present tabulations of the new safety data combined with the original NDA\ndata.\n\ne Include tables that compare frequencies of AE in the original NDA with the\nretabulated frequencies described in the bullet above.\n\ne For indications other than the proposed indication, provide separate tables for\nthe frequencies of AEs occurring in clinical trials.\n\nNDA 217724/Original 1\nPage 4\n\n(3) Present a retabulation of the reasons for premature trial discontinuation by\nincorporating the dropouts 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 AE. In\naddition, provide narrative summaries for SAEs.\n\n(5) Describe any information that suggests a substantial change in the incidence of\ncommon, but less serious AEs between the new data and the original NDA 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 the drug. Include an\nupdated estimate of use for drug marketed in other countries.\n\n(8) Provide English translations of current approved foreign labeling not previously\nsubmitted.\n\nADDITIONAL COMMENTS\n\nWe have the following comments and requests for additional information that are not\napprovability issues. However, we request you submit your responses with your\ncomplete response to this letter.\n\nReference ID: 5459701\n\n(1) We note that age and body weight are covariates for dasiglucagon exposure.\nThe lowest body weight enrolled in study 17103 was 4.1 kg. Therefore, no\nclinical data was generated for infants < 4.1 kg.\n\nYou have not described any information regarding body weight in Section 2\nDosage and Administration of the submitted draft P|. Clarify how prescribers\nshould consider body weight when determining the dose of dasiglucagon.\nSubmit your proposal (i.e., draft Pl language) and justification with supporting\ndata for Section 2 Dosage and Administration regarding the impact of age\nand body weight on dasiglucagon dosing.\n\nFurthermore, we note that the simulated 95% confidence interval (Cl) upper\nlimit of dasiglucagon exposures (based on 70 microgram/hour dose) for body\nweight < 4.1 kg is anticipated to exceed the peak plasma exposure of 3.78\nnmol/L at the no observed adverse effect level (NOAEL) for the transient\nfreezing absences in rats. Provide a justification with clinical safety data to\nsupport a dosing recommendation for infants < 4.1 kg.\n\nNDA 217724/Original 1\nPage 5\n\n(2) You propose to limit the indication statement based on chronological age i.e., to\npediatric patients with CHI who are at least 7 days old.\n\ne We note that study 17103 excluded infants with chronological age < 7 days.\nClarify whether you anticipate any differences in the overall benefit/risk\nassessment in infants < 7 days of age (including premature infants) as\ncompared to those 2 7 days of age.\n\ne Clarify if you are proposing to include premature and term infants in the\nproposed indication.\n\ne We note that study 17103 excluded subjects < 34 weeks of gestational age.\nClarify if any premature infants were enrolled in study 17103.\n\n(3) Comment on safety and efficacy considerations in small for gestational age\n(SGA) and premature infants compared to term infants. Specifically, address the\nfollowing:\n\ne Provide information on the impact of incomplete kidney development and\nimmature kidney physiology in premature infants on dasiglucagon\npharmacokinetic (PK) characteristics compared to term infants with similar\nbody weight.\n\ne Provide information on the impact of possible limited hepatic glycogen stores\nin SGA and premature infants on efficacy of continuous subcutaneous (SC)\nadministration of dasiglucagon up to 3 weeks.\n\ne Provide your justification for safety of continuous SC administration of\ndasiglucagon up to 3 weeks in SGA and premature infants. Clarify how the\nsafety profile of dasiglucgon may differ between SGA and premature and\nterm infants and if SGA and premature infants may be at increased risk of\ndrug-related AEs due to physiologic immaturity. For example, we note that\nAEs of hyponatremia, thrombocytopenia and metabolic acidosis have been\ndescribed in the literature as possibly associated with the off-label use of\nglucagon products in premature and low birth weight infants‘.\n\nIn addition, provide your justification for safety of dasiglucagon in infants <\n4.1 kg considering the simulated 95% Cl upper limit of dasiglucagon\nexposures (based on 70 microgram/hour dose) for body weight < 4.1 kg is\nanticipated to exceed the peak plasma exposure of 3.78 nmol/L at NOAEL\nfor the transient freezing absences in rats.\n\n4 Belik J, at al. Pediatrics. 2001 Mar;107(3):595-7; Charsha DS, et al. Pediatrics. 2003 Jan;111(1):220-1;\nHoban R, et al. Paediatr Child Health. 2022 Sep 8;28(1):24-29.\n\nReference ID: 5459701\n\nNDA 217724/Original 1\nPage 6\n\ne Provide any other data and information related to the above request.\n\n(4) Provide a justification for use of the infusion pump and infusion set in infants <\n4.1 kg, including in premature infants. Clarify if you anticipate any technical\nchallenges in inserting and/or maintaining the infusion pump and infusion set in\nlower weight or premature infants due to limited SC fat.\n\n(5) The effect of moderate to severe renal impairment on dasiglucagon PK has not\nbeen investigated. Submit your proposal for the product PI regarding renal\nimpairment with justification and supporting data.\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\n\nhis 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\n‘ake 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 drug product may not be legally marketed until you have been notified in writing\nhat this application is approved.\n\nReference ID: 5459701\n\nNDA 217724/Original 1\nPage 7\n\nSincerely,\n\n{See appended electronic signature page}\n\nCenter for Drug Evaluation and Research\n\nReference ID: 5459701\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\n10/08/2024 04:31:33 PM\n\nReference ID: 5459701\n",
      "application_number": [
        "NDA 217724/Original 1",
        "NDA 217724"
      ],
      "letter_type": "COMPLETE RESPONSE"
    }
  ]
}