Critical Dates after NDA/BLA submission: Filing Date (Day 1), Day 14, Day 60, Day 74, and PDUFA date

After the NDA/BLA is submitted to FDA, the FDA review clock starts. There are several critical dates relevant to the applicant (the sponsor).

Filing date (Day 1): the date that the NDA/BLA application is received by FDA. Nowadays, the NDA/BLA submission will be in eCTD format and go through FDA's electronic submission gateway. FDA will receive the NDA/BLA submission on the same day (or the next day) as the sponsor submits. The review clock (or PDUFA time clock begins when the application is received by the FDA. 

Day 14: FDA acknowledges to the sponsor in writing (filing letter) that the application is received. Between Day 1 - Day 14, the FDA could request the sponsor to correct the conformance issues. For example, the data sets in the SAS transport file were created using incorrect procedures and could not be opened by the FDA. FDA would ask the sponsor to resubmit the data sets in the SAS transport file using the correct procedures. 

Filing Letter – a letter issued to notify the applicant that their submission has been filed and will be reviewed. Note: The filing letter also includes information stipulated by PDUFA and may contain any identified filing deficiencies.

According to OFFICE OF MANAGEMENT: Effect of Failure to Pay BsUFA Fees

If the applicant (including its affiliates) is not in arrears and has satisfied any fee requirements for the application, then the RPM /RBPM aligned with the review division sends an Acknowledgement Letter within 14 calendar days of receipt of submission to the applicant.

Day 60: The sponsor will be notified within 60 days of submitting the NDA/BLA whether the application has been accepted for filing (or conversely, if the FDA refuses to file the application due to lack of information or studies).

According to CDER 21st Century Review Process Desk Reference Guide, by Day 60, FDA needs to: 

• Inform the applicant of a Priority Designation in Writing Communicate Filing Determination to Applicant (for BLAs and priority NDAs) 
• Notify Applicant of a Refuse-to-File determination. Communicate an RTF action to the applicant by day 60 in the form of official correspondence. Refusal to file (RTF) is the Food and Drug Administration (FDA)’s formal decision to deny review of a New Drug Application (NDA), Biologics License Application (BLA), supplemental NDA (sNDA) and supplemental BLA (sBLA) due to application deficiencies. 

If the sponsor requested for priority review and did not receive a notification by Day 60, it is most likely that the priority review was not granted by the FDA. The standard review (10-months) will follow. 

Day-74 (Deficiencies Identified) Letter – a letter notifying the applicant of issues identified during the filing review phase that were not communicated in the filing letter. It is likely that the issues related to the statistical analyses will be included in the Day-74 letter. 

According to PDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROCEDURES FISCAL YEARS 2018THROUGH 2022:

Day 74 Letter: FDA will follow existing procedures regarding identification and communication of filing review issues in the “Day 74 letter.” For applications subject to the Program, the timeline for this communication will be within 74 calendar days from the date of FDA receipt of the original submission. The planned review timeline included in the Day 74 letter for applications in the Program will include the planned date for the internal mid-cycle review meeting. The letter will also include preliminary plans on whether to hold an Advisory Committee (AC) meeting to discuss the application. If applicable, the Day 74 letter will serve as notification to the applicant that the review division intends to conduct an expedited review.

Review performance goals: For NME NDA and original BLA submissions that are filed by FDA under the Program, the PDUFA review clock will begin at the conclusion of the 60 calendar day filing review period that begins on the date of FDA receipt of the original submission. 

Day 74 Letter: If the application is accepted for filing (60 days after submission), then the sponsor will receive an FDA 74-day letter, which contains a planned NDA review timeline that varies based on several factors such as whether other similar drugs already exist or whether your drug treats an unmet medical need.

The FDA 74-Day letter also confirms your action date (PDUFA date), confirms standard versus priority review, and identifies any preliminary deficiencies in your application. Sponsors must act quickly to resolve the deficiencies noted in the FDA 74-day letter during the NDA review process.

According to CDER 21st Century Review Process Desk Reference Guide, by Day 74 (i.e., Day 60 + 14 Days), FDA needs to:

•  Communicate Filing Review Issues
•  Communicate “Program” Review Timeline to Applicant (if applicable)

According to MAPP: OFFICE OF NEW DRUGS  Review Designation Policy: Priority (P) and Standard (S), the sponsor will be informed of the priority review designation by Day 60. If the sponsor is not notified of the priority review designation by Day 60, it means that the request for priority review is not granted, and the standard review designation will be applicable. 

The division will inform the applicant in writing of a priority review designation by Day 60 of the review. The division will inform the applicant of a standard review designation in the filing communication by Day 74 of the review.

PDUFA date (FDA action date): 

Prescription Drug User Fee Act (PDUFA) dates refer to deadlines for the FDA to review new drugs. The PDUFA date is 10 months after the drug application has been accepted by the FDA or 6 months, if the drug is given a priority review designation.

By the PDUFA date, FDA needs to notify the sponsor if its NDA/BLA application is approved, tentative approved (pending the patent issues or exclusivity issues), or given a complete response letter (CRL). FDA issues a CRL when declining the NDA/BLA. The CRL will include the reasons why the FDA can not approve the NDA/BLA in its current format. 

Notice that the PDUFA date (6 months for priority review and 10 months for standard review) may not be calculated from the filing date (day 1), but rather is calculated from Day 60 after the filing date - this essentially adds two months to the review timeline. Two months are necessary for FDA to conduct the initial review to decide if the application is reviewable. With these two months (60 days), the PDUFA date may actually be 8 months for some applications with priority review designation and 12 months for standard review after the sponsor submits the NDA/BLA. 

The initial scheduled PDUFA date will be extended if additional data or materials are submitted during the review period, which constitutes a major amendment to the NDA/BLA submission. 

This Youtube video explained very well about NDA and BLA Application Review Process as part of the REdI Annual Conference (2019)

I have collected some recent NDA/BLA (or supplemental NDA/BLA) submissions to see when FDA notification date is relevant to the submission date and how the PDUFA date is determined. 

	Submission date/filing date	FDA notification date	PDUFA date	Actual Decision Date
Akebia NDA for Vadadustat for the Treatment of Anemia Due to Chronic Kidney Disease	March 30, 2021	June 1, 2021   By Day 60	March 29, 2022 Standard review – 10 months from Day 60	March 30, 2022   CRL was issued
Amarin sNDA for VASCEPA® for cardiovascular risk reduction	March 28, 2019	May 29, 2019   By day 60	September 28, 2019 Priority Review – 6 months from the filing date	December 13, 2019 Approved, 3 months of delay due to conducting Adcomm
Amylyx NDA for AMX0035 for the Treatment of ALS	November 2, 2021	December 29, 2021   By Day 60	June 29, 2022   Priority review – 6 months from Day 60	September 29, 2022 Approved 3 months of delay due to conducting two rounds of Adcomm
Blueprint Medicines sNDA  for AYVAKIT® for the Treatment of Indolent Systemic Mastocytosis	November 22, 2022	January 23, 2023   By Day 60	May 22, 2023   Priority review – 6 months from the filing date
Acadia Pharmaceuticals NDA for Trofinetide for the Treatment of Rett Syndrome	July 18, 2022	September 12, 2022   Within Day 60	March 12, 2023   Priority review – 6 months from Day 60
Argenx BLA for efgartigimod for treatment of generalized Myasthenia Gravis	September 21, 2022	November 22, 2022   By Day 60	March 20, 2023   Priority review – 6 months from the filing date
Cidara Therapeutics NDA for Rezefungin for treatment of Candidemia and invasive candidiasis	July 27, 2022	September 20, 2022 Within Day 60	March 22, 2023   Priority review – 6 months from Day 60
Ionis with Biogen NDA for tofersen for ALS		July 26, 2022	Jan. 25, 2023 Priority review – 6 months from Day 60
Biomarin BLA Gene Therapy for Hemophilia A	September 29, 2022 Resubmission	October 12, 2022	March 31, 2023 6 months from resubmission date
Gamida cell BLA for Omidubicel for hematologic and solid cancer	June 2, 2022	August 1, 2022   By Day 60	January 30, 2023 Priority review – 6 months from Day 60	PDUFA date is further extended by 3 months to May 1, 2023
Ascendis Pharma	August 31, 2022	October 31, 2022   By Day 60	April 30, 2023 Priority review – 6 months from Day 60
Biomarin BLA Gene Therapy for Hemophilia A	December 23, 2019	February 20, 2020 By Day 60	August 21, 2020 Priority review - 6 months from Day 60	August 18, 2020   CRL was issued
Arcutis’ ZORYVE™ (Roflumilast) Cream 0.3% For the Treatment of Plaque Psoriasis	October 4, 2021	December 22, 2021 By Day 74	July 29, 2022 Standard review – almost 10 months from filing date	July 29, 2022   approved
Apellis NDA for Pegcetacoplan for Geographic Atrophy	June 1, 2022	July 19, 2022   Within Day 60	November 26, 2022 Priority review – Less than 6 months from the filing date	February 17, 2023 Approved, Almost three months of delay due to a major amendment to the NDA (additional submission of long-term data)
TG Therapeutics BLA for Umbralisib for treatment of Lymphoma	June 17, 2020	August 13, 2020   With Day 60	February 15, 2021 Priority review – 6 months from Day 60	February 5, 2021 Approved, Then FDA withdrew the approval
Reata Pharmaceutics NDA for omaveloxolone for the Treatment of Friedreich’s Ataxia	March 31, 2022	May 26, 2022   Within Day 60	November 30, 2022 Priority review – 6 months from the filing date	February 28, 2023 Approved,  5 months of delay due to a major amendment to include the OLE data
Prevention Bio BLA for Teplizumab for Type 1 Diabetes	November 2, 2020	January 4, 2021   By Day 60	July 2, 2021 Priority review – 6 months from Day 60	July 2, 2021 CRL was issued
Liquidia NDA LIQ861 for treatment of PAH	January 27, 2020	April 8, 2020   By Day 74	November 24, 2020 Standard review – 10 months from the filing date	November 25, 2020 CRL was issued
Horizon sBLA for KRYSTEXXA® for Uncontrolled Gout	January 10, 2022	March 7, 2022   Priority review -	July 7, 2022 Priority review – 6 months from the filing date	July 8, 2022   Approved