While most marketing applications rely heavily on data from pivotal phase 3 trials, what do we do if that efficacy study continues past the timepoint for primary analysis? What if the protocol includes an open-label extension? Do we wait to submit until after the study is completed?

Regulatory reviewers will expect a Clinical Study Report (CSR) and supporting electronic data packages for these studies, but that doesn’t have to delay our filing date. Below are some suggested techniques to provide the agency with everything they need to review the application, without compromising the integrity of the ongoing study.

Freeze the Data
Just as we often do for an interim analysis, resolve any queries up to and including the primary endpoint visit, then freeze those data. This will ensure that the data used for primary efficacy analyses are source verified, free of errors, and cannot be altered at a later date. But subsequent visits for those same subjects can still be entered and edited.

SDTM/ADaM from Frozen Data
The sponsor can choose to submit only the clean data up to the primary endpoint visit, or to include all data collected. But CDISC-compliant data packages should be submitted to facilitate regulatory review, including data definition files (define.xml) and data reviewer’s guides for both SDTM and ADaM. These supporting documents can be used to specify how the freeze was implemented, and what submitted data are/are not cleaned.

Don’t Forget to Update TS!
Many teams draft the Trial Summary domain (ts.xpt) as it would look at the end of the study. But don’t forget to update the parameters to match how the ongoing study data is included. Pay close attention to the Data Cutoff Description (DCUTDESC) and Data Cutoff Date (DCUTDTC).

Clinical Study Report
A complete CSR should be submitted, describing all safety and efficacy data collected and analyzed up to and including the primary endpoint visit. This is a great location to provide a detailed justification for why data is being submitted for an ongoing study.

Safety Update
After the study ends and the final database is locked, plan to submit an updated set of SDTM/ADaM, along with an amended CSR to summarize the study as a whole. This can be done at the 120-day safety update, or at a later date, depending where database lock falls in your filing timeline.

As always, discuss the plan for submitting ongoing study data with your review division as early as possible to avoid impacting the timeline.

Questions about how to prepare a marketing application with ongoing studies? Contact us to speak with one of our Biometrics Regulatory Experts.

Evan Zucker, Principal Biostatistician, has 8 years of experience providing statistical support for clinical trials, with a specific focus on late-stage regulatory submissions. Mr. Zucker has supported upwards of twenty marketing applications and over a dozen FDA meetings, often working as the primary author of integrated statistical analysis plans and CDISC-compliant integrated analysis dataset (ADaM) specifications for the ISS and ISE. In supporting marketing application submissions, he also acts as a data standards expert, reviewing and updating study data packages to ensure compliance with the latest FDA requirements, technical rejection criteria, and CDISC/legacy guidelines. Mr. Zucker has collaborated with clinical researchers and medical authors across various therapeutic areas, including pain/anesthesia, psychiatry, otolaryngology, oncology, ophthalmology, rare/genetic diseases, and vaccines/infectious diseases.