Introduction
The submission of a New Drug Application (NDA) to regulatory authorities and its subsequent approval is an important milestone in the lifecycle of a drug, potentially leading to a novel or alternative treatment option for patients with severe diseases.
About 73% of all NDAs are eventually approved. The most common reasons for unsuccessful first-time applications are safety concerns, lack of efficacy or inconsistent results. The priority the FDA assigns to an NDA and the experience of its sponsor influence the timing and likelihood of approval. FDA reviewers assess the application at the time of submission for completeness and compliance with applicable standards and guidelines. To meet all statutory requirements, sponsors need partners with expertise in data management, biostatistics, and medical writing to provide professional services and ensure a high-quality submission.
In 2019, BiolineRx, a pre-commercial-stage biopharmaceutical company focused on oncology, published in Future Oncology the phase III study results from the GENESIS trial on motixafortide (BL-8040), a new CXCR4 inhibitor providing robust stem cell mobilization in patients with multiple myeloma. When preparation of an NDA was required, BiolineRx went into partnership with Bioforum to continue the project, which was previously managed by a different CRO. Preparation of the submission package in accordance with all applicable standards was the goal of this collaboration. Three key teams of Bioforum professionals were involved in the project – Data Management, Statistical Programming, and Medical Writing.
Challenge
A thorough investigation of database quality, identification of risk areas, and amendment of the database to comply with protocol requirements was performed according to data management best practices. The structural complexity of the study, comprising two consecutive parts, one of which had already been completed, and data “rescue” were among the challenging hurdles faced by Bioforum’s Data Management (DM) team. Alignment to study structure also had to be preserved from the clinical point of view to ensure data consistency. Since this was during the “live” phase of the study, with partial data being entered, the main purpose of DM was to ensure data integrity.
The biostatisticians faced challenges with SDTM mapping, conversion programming, and data migration, together with multiple CRF amendments, while having to be compliant with all CDISC guidelines.
Medical writers faced different challenges related to the preparation of the clinical study report (CSR), presenting data from the first part of the study. Many of the source documents (TFLs) were updated multiple times during the project, leading to the repeated need to change the description of the findings in the CSR, which was drafted as an abbreviated report. Due to tight timelines defined by the Sponsor, QC work and implementation of comments by the medical writers were carried out simultaneously. Ultimately, a CSR meeting both internal Bioforum expectations as well as those of the Sponsor was provided.
Solution
Data Management carried out numerous tasks to mitigate the risks in accommodating timelines with real data. Converting data from the single legacy study to CDISC standards (SDTM/ADaM) to ensure consistency across all clinical trial results was the first step taken by Bioforum’s team of experts. Biostatisticians worked closely with the BiolineRx team to ensure proper SDTM mapping, conversion programming, and QC for the preparation of all submission packages. Our team of biostatisticians performed QC and output validation on the analysis, during preparation of the ADaM datasets, and prior to full submission of all packages for the GENESIS study. In addition, the team prepared the electronic submission package for all of BiolineRx’s legacy projects, following all the technical rules. Medical writers used the same approach. Data presentation was agreed upon and highlighted as per the Sponsor’s preferences by maintaining collaboration with the BiolineRx team. Internal collaboration with the DM team ensured quick alignment and provided an opportunity for open questions to be resolved. The well-established review process of Bioforum helped to raise important issues to be solved by communication between BiolineRx and Bioforum DM teams.
For the GENESIS study, Bioforum’s biostatisticians prepared two submission packages with core study data, and two packages with 1-year-lock study data.
Results
BiolineRx submitted its NDA for motixafortide in September 2022, and an FDA decision is expected in November of this year. Assuming the filing is accepted, the potential PDUFA date would be in Q2 2023 (under a priority review process, if applicable) or Q3 2023 (under a standard review process). We believe that the clear, consistently formatted, and thoroughly documented study packages prepared by Bioforum will contribute to a seamless regulatory review process.
We are proud to have partnered with BiolineRx in their endeavor to provide a new therapeutic option for patients with multiple myeloma. This successful partnership was based on close collaboration with the Sponsor as well as on the internal cross-functional communication of our experts.
Abbreviations used in the text: ADaM (Analysis Data Model); CDISC (Clinical Data Interchange Standards Consortium); CRF (Case Report Form); CRO (Clinical Research Organization); CSR (Clinical Study Report); DM (Data Management); FDA (US Food and Drug Administration); NDA (New Drug Application); STDM (Statistical Time Division Multiplexer); TFLs (Tables, Figures, and Listings); QC (Quality Control).