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 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.
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.
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Submission date/filing date
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FDA
notification date
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PDUFA date
|
Actual Decision
Date
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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
|
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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
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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
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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
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