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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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    {
      "letter_date": "04/27/2021",
      "approver_title": "Director",
      "file_name": "761161_2023_Orig1s000OtherActionLtrs.pdf",
      "letter_year": "2021",
      "approval_status": "Approved",
      "approver_name": "Hylton V. Joffe, MD, MMSc",
      "approver_center": [
        "Center for Drug Evaluation and Research"
      ],
      "company_rep": "Matt Medlin, PhD, RAC",
      "company_address": "175 Regency Woods Place, Suite 600\nCary, NC 27518",
      "company_name": "Chiesi USA",
      "text": "m4 YN U.S. FOOD & DRUG\n\nADMINISTRATION\n\nBLA 761161\nCOMPLETE RESPONSE\n\nChiesi USA\n\nAttention: Matt Medlin, PhD, RAC\n\nSr. Manager, US Regulatory Affairs R&D\n175 Regency Woods Place, Suite 600\nCary, NC 27518\n\nDear Dr. Medlin:\n\nPlease refer to your biologics license application (BLA) dated and received May 27,\n2020, and your amendments, under section 351(a) of the Public Health Service Act for\nPRX-102.\n\nWe acknowledge receipt of your major amendment dated November 4, 2020, which\nextended the goal date by three months.\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\nDEFICIENCES AND INFORMATION NEEDED TO RESOLVE THE DEFICIENCIES\n\n1. Facilities\n\nDuring a review of records requested under section 704(a)(4) of the Federal\nFood, Drug, and Cosmetic Act, we communicated issues with the oy\nmanufacturing facility named in your\n\napplication. Satisfactory resolution of the remaining issues is required before this\napplication may be approved. We will communicate the outstanding issues to the\nfacility no later than 10 business days after issuing this complete response letter.\nContact the © manufacturing\nfacility for additional information.\n\n2. Use of the Accelerated Approval Pathway When There is Available Therapy\n\nYou requested accelerated approval of PRX-102 based on a reduction in renal\nperitubular capillary globotriaosylceramide (Gb3) inclusions. As previously\ncommunicated on March 15, 2021, with the full approval of Fabrazyme\n\nReference ID: 4786555\n\nBLA 761161\nPage 2\n\n(agalsidase beta) on March 11, 2021, Fabrazyme is now available therapy? for\nFabry disease. Your product will no longer qualify for accelerated approval if it\ndoes not provide a therapeutic advantage over available therapy. We\nacknowledge your response dated March 26, 2021. Given the late timing of this\ndevelopment in the review cycle we have not completed our review of that\namendment.\n\nPrior to your resubmission, we recommend an End-of-Review meeting to discuss\nwhether accelerated approval remains an appropriate pathway for your product.\nThat discussion should also include a status update on your ongoing intended\nconfirmatory postmarketing trial, and your assessment of the likelihood that this\ntrial will be able to show superiority of your product to Fabrazyme on eGFR\nbased on what is known with regard to the effects of these products on renal Gb3\ninclusions, and your plans should that trial fail to show superiority of PRX-102\nover Fabrazyme.\n\nAn alternative approach to seeking accelerated approval may be to establish that\nthe reduction in renal Gb3 inclusions with PRX-102 predicts clinical benefit,\nallowing for full approval of your product. Data to support such an approach\nshould show that:\n\n¢ Gb3 is toxic to tissues when it accumulates\n\ne Gb3 accumulates in all tissues where Fabry disease causes structural\ndamage and functional loss\n\ne The degree of Gb3 accumulation is correlated with the degree of tissue\ndamage\n\ne Areduction in Gb3 is associated with normalization of structure and\nfunction\n\ne PRX-102 sufficiently removes Gb3 from Fabry target tissues, including in\nwomen.\n\nWe recommend also discussing whether full approval may be a possible path\nforward for your product at the End-of-Review meeting.\n\n1 https:/Awww.fda.gov/regulatory-information/search-fda-quidance-documents/expedited-programs-\n\nserious-conditions-drugs-and-biologics\n\n2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance\nDocuments Database hitps://www.fda.gov/RegulatoryInformation/Guidances/default.htm.\n\nU.S. Food and Drug Administration\n\nSilver Spring, MD 20993\n\nwww.fda.gov\n\nReference ID: 4786555\n\n\nBLA 761161\nPage 3\n\nPRESCRIBING INFORMATION\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 PLR\nRequirements for Prescribing Information’ 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\ne The 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 Selected Requirements for Prescribing Information (SRPI) - a checklist of\nimportant format items from labeling regulations and guidances.\n\nFDA's established pharmacologic class (EPC) text phrases for inclusion in the\nHighlights Indications and Usage heading.\n\nSubmit draft labeling that addresses our proposed revisions in the attached labeling.\n\nPrior to resubmitting the labeling, use the SRPI checklist to correct any formatting\nerrors to ensure conformance with the format items in regulations and guidances. In\naddition, submit updated content of labeling [21 CFR 601.14(b)] in structured\nproduct labeling (SPL) format as described 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\nPROPRIETARY NAME\n\nRefer to correspondence dated, February 17, 2021, which addresses the proposed\nproprietary name, Elfabrio. This name was found acceptable pending approval of the\n\n3 http:/Awww.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/LawsActsandRules/ucm08415\n9.htm\n\n4 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/Labeling/ucm09330\nZhtm\n\n5 http://www.fda.gov/Forlndustry/DataStandards/StructuredProductLabeling/default.htm\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 4786555\n\nBLA 761161\nPage 4\n\napplication in the current review cycle. Resubmit the proposed proprietary name when\nyou respond to the application deficiencies.\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 product 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 patient 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 product. Include\nan updated estimate of use for product marketed in other countries.\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 4786555\n\nBLA 761161\nPage 5\n\n(8) Provide English translations of current approved foreign labeling not previously\nsubmitted.\n\nADDITIONAL INFORMATION\n\n1. In addition to responding to the deficiencies presented above, please note and\nacknowledge the following comment in your response.\n\nAn inspection of the Protalix Ltd. (FEl# 3008289067), Carmiel, Israel\nmanufacturing facility is required before this application can be approved. FDA\nmust assess the ability of that facility to conduct the listed manufacturing\noperations in compliance with CGMP. Due to restrictions on travel, we were unable\nto conduct an inspection during the current review cycle for your application. You\nmay respond to deficiencies in this Complete Response Letter while the travel\nrestrictions remain in effect. However, even if these deficiencies are addressed,\nthe application cannot be approved until the required FDA inspection is conducted\nand any findings are assessed with regard to your application. We will continue to\nmonitor the public health situation as well as travel restrictions. We are actively\nworking to define an approach for scheduling outstanding inspections, once safe\ntravel may resume and based on public health need and other factors.\n\nFor more information, see the FDA guidances related to COVID 19.°\n2. Infusion-Related Reactions\n\nIt is unclear why you chose a window of only 2 hours after PRX-102\nadministration for defining an infusion-related reaction. You also have not\nprovided sufficient reasoning for excluding adverse events that you considered\nrelated to the infusion procedure rather than PRX-102. You have also not\nprovided a clear narrative regarding premedication that was given in your safety\ndatabase. Therefore, in the next review cycle include:\n\n« Adataset and assessment of all infusion-related reactions that occurred\nwithin 24 hours of PRX-102 administration.\n\ne Provide additional details on each of the excluded events that you attributed\nto the infusion procedure, including the investigator verbatim term, any\nadditional clinical details, and your basis for determining that they were\nrelated to the infusion procedure and not PRX-102.\n\ne Patient narratives on every subject in the safety database who required\npremedication (specifically what medications were given) with an explanation\nof why they were given premedication.\n\n6 https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/covid-\n19-related-guidance-documents-industry-fda-staff-and-other-stakeholders\n\nU.S. Food and Drug Administration\n\nSilver Spring, MD 20993\n\nwww.fda.gov\n\nReference ID: 4786555\n\nBLA 761161\nPage 6\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 601.3(b). If you do not take one of these actions, we\n\nmay consider your lack of response a request to withdraw the application under\n\n21 CFR 601.3(c). 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\nIf you have any questions, call Michael G. White, PhD, Chief, Project Management\nStaff, at 240-402-6149.\n\nSincerely,\n{See appended electronic signature page}\n\nHylton V. Joffe, MD, MMSc\n\nDirector\n\nOffice of Rare Diseases, Pediatrics,\nUrologic and Reproductive Medicine\nCenter for Drug Evaluation and Research\n\nENCLOSURE:\ne Labeling\n\n17 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this\npage\n\nU.S. Food and Drug Administration\nSilver Spring, MD 20993\nwww.fda.gov\n\nReference ID: 4786555\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\nHYLTON V JOFFE\n04/27/2021 07:47:46 PM\n\nReference ID: 4786555\n",
      "application_number": [
        "BLA 761161"
      ],
      "letter_type": "COMPLETE RESPONSE"
    }
  ]
}