120-Day Safety Update or 4-Month Safety Update - The Requirement for NDA/BLA

After the new drug application (NDA) or biological license application (BLA) is submitted by the sponsor and is accepted by FDA, FDA reviewers will take 10 months (regular review) or 6 months (expedited review) to review the submission package and issue a decision on or before the decision date (PDUFA date). FDA reviewers will evaluate marketing applications for efficacy and safety and consider benefit and risk and will expect to receive a complete application at the time of filing (exclusive of the 120-day safety update).

It is very possible that during the 6-10 month review time, the sponsor will have additional data to supplement the already submitted NDA/BLA package. The regulatory pathway for providing additional data to the FDA is through so-called ‘120-Day Safety Update’, also referred to as ‘4-Month Safety Update, 4MSU).

The ‘120-Day Safety Update’ or ‘4-Month Safety Update” is specified as a requirement in Code of Federal Regulations - 21CFR314.50.

 

The 120-Day Safety Update contains any new safety information learned about the drug that may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft drug labeling.

The report must be received by the FDA within 120 days of drug approval submission (receipt by the FDA of the New Drug Application (NDA), comprising the CTD/Integrated Summary Report) to avoid triggering an extension of the review clock.

The 120-Day Safety Update Report is mandated for submission to the FDA 120 days after submission of the NDA/BLA, and is intended to provide a summary update of any new safety data gathered by the sponsor since the data cut-off for the NDA submission documents, which could have been as far back as 6 months prior to the NDA submission date. In effect, the 120-Day Safety Update report could represent almost 1 year’s worth of new safety data, which needs to be reviewed by the authorities to ensure there has been no change in the product’s recorded safety profile. This is particularly important for medications intended for long-term treatment.

The 120-Day Safety Update is focused on additional safety data. If additional data is collected for efficacy variables, the efficacy information can also be included - but in general, it is for the summary propose and there is no inferential statistics needed. 

The data to be included in the 120 Day Safety Update can include:

• The long-term follow-up data from the on-going clinical trials
• Open-label extension studies with patients rolled over from the pivotal studies (usually the double-blinded controlled studies)
• Additional data from later time points and from newly enrolled patients
• Newly initiated clinical trials

Depending on the type of data to be included in the 120 Day Safety Update, the submission package could be just a written report or a full submission package (including the report; post-text tables, listings, figures; the data sets; define documents; SDRG/ADRG, etc.).

There are a lot of examples of 120 Day Safety Update from market applications. Here are some examples:

Briefing Document for Advisory Committee Meeting on Novo Nordisk’s Insulin degludec/liraglutide (IDegLira) for Treatment to Improve Glycemic Control in Adults with Type 2 Diabetes Mellitus. The NDA submission was based on two pivotal trials. Two pivotal trials (Trial 3697 in patients inadequately controlled on OAD treatment and Trial 3912 in patients inadequately controlled on basal insulin treatment) were designed to assess the contribution of the individual components of the combination to its primary efficacy effect (i.e., overall glycemic control). Additional data from other ongoing studies and the studies initiated after the data cut for NDA submission were submitted to the NDA as ‘120 Day Safety Update’:

The NDA submitted to the FDA had a data cut-off of 31 March 2015. Additional blinded safety data from two phase 3 trials that were ongoing at the time of NDA submission (Trials 4119 and 4056) as well as from a trial that was subsequently initiated (Trial 4185) was submitted to the FDA in a 120 Day Safety Update with a cut-off date of 30 September 2015. A brief overview of the ongoing trials included in the 120-day safety update is provided in Table 1–1. The 120-day safety update included available blinded safety data from these trials on deaths, other serious adverse events, pregnancies (including updates for pregnancies reported as ongoing in the NDA) and adverse events leading to withdrawal. 

Sunovion Pharmaceuticals NDA of Latuda for treatment of major depressive episodes associated with bipolarI disorder in pediatric patients aged 10 and older. The NDA submission was mainly based on the pivotal study (Study D1050326). Subjects who completed Study D0150326 was recruited into an open-label study (D1050302). As a 120-day safety date, the date from the open label study was submitted to support the NDA.

Study D1050302 is a 104-week open-label trial designed to assess the long-term safety profile of lurasidone (dosed 20-80 mg per day) in pediatric patients recruited from the pediatric schizophrenia (Study D1050301), bipolar depression (Study D1050326), and autism trials. This study was scheduled for completion last December, 2017. The Applicant submitted preliminary data for 619 patients participating in this trial with a cutoff date of October, 2016. Additionally, the 120-day safety update submitted with this application focused on the available safety data from 305 patients recruited from Study D1050326 with a cutoff date of May, 2017. It should be noted that although the final report for Study D1050302 has not been submitted for review, the Applicant presented acceptable long-term data to make an approval determination for this sNDA, including lurasidone exposure of 153 patients for ≥ 52 weeks.

Clinical Review for BLA for Mepolizumab for Add-on maintenance treatment of severe asthma. The data from long-term open-label studies were not available at the time of BLA preparation but was submitted to FDA as a 120-Day Safety Update.

This safety review primarily relies on data from three placebo-controlled studies in a severe asthma population: MEA112997 (Study 97), MEA115588 (Study 88) and MEA115575 (Study 75) as these studies most closely approximate the patient population to receive mepolizumab in the clinical practice. Within this review, the pooled database for these studies is referred to as the Placebo-Controlled Severe Asthma Studies (PCSA). Longer term safety data are provided by two open-label studies, MEA115666 (Study 66), MEA115661 (Study 61). These studies were ongoing at the time of the BLA submission with updated data provided to the Division in a 120-day safety update. The data from this safety update used a cutoff date of October 27, 2014 and provides cumulative review of the data for the studies ongoing at the time of BLA submission25 .