Regulatory submissions are the most critical milestones in clinical research programs. Quality submissions can accelerate time to market, maximize research investments and bring the benefit of new treatments to patients sooner.
In August 2018, when the time came for RedHill Biopharma (Nasdaq: RDHL) to prepare its New Drug Application (NDA) for Talicia® (omeprazole magnesium, amoxicillin and rifabutin), the specialty biopharmaceutical company turned to Bioforum’s team of experts to prepare key components of the regulatory submission. Approved by the FDA for the treatment of H. pylori in adults in November 2019, Talicia® is the only available rifabutin-based therapy that addresses the growing resistance of H. pylori bacteria to current clarithromycin-based standard-of-care therapies.
RedHill needed a trusted partner to prepare its integrated summary of safety and integrated summary of efficacy (ISS and ISE respectively) submission packages. These are more than just summaries, as the name might suggest. They bring together the findings of all of the clinical trials performed on the study drug, which are then analyzed as a whole to produce combined statistical results. As such, ISS and ISE submissions are multifaceted, crucial components of an NDA, and they are required by the FDA.
In order to integrate data from one study into a larger dataset from other studies, all data must be formatted the same way. Clinical Data Interchange Standards Consortium (CDISC) provides a set of standards for organizing clinical trial data, including the Study Data Tabulation Model (SDTM) and the Analysis Data Model (ADaM). Today, the FDA Data Standards Catalog specifies the use of CDISC standards as a requirement. However, because it was not mandatory to apply CDISC standards prior to 2017, many older studies are initially only available in the legacy (non-CDISC) format. This was the case for one of the earlier RedHill studies, which had been completed prior to the CDISC standards requirement and needed to be converted so that it could be included in the ISS and ISE submission packages.
Without a thorough conversion of a legacy study that meets all CDISC requirements, a sponsor could risk missing key deadlines and delaying the submission timelines to the FDA and other regulatory agencies. Incomplete SDTM or data quality issues in SDTM could also impact ADaM data, which would ultimately impact the ease with which the FDA can trace source data to reproduce the analysis results. And if the data does not pass the published CDISC compliance checks and FDA’s data fitness tests, a sponsor could receive a refusal to file (RTF) from regulatory authorities, opening the door to further delays.
To help RedHill avoid these issues and prepare a successful NDA, Bioforum would need to quickly convert the legacy study to the CDISC format. More broadly, Bioforum would also need to uncover and reconcile any inconsistencies in the data format, domain assumptions and data mapping across all the clinical trials associated with the study drug.
The first step Bioforum’s team of experts took was converting data from the single legacy study to CDISC standards (SDTM/ADaM), ensuring consistency across all clinical trial results included in the ISS and ISE submission packages. Bioforum had to carefully investigate what was done in the legacy study and clarify what assumptions RedHill’s former CRO partner made while programming outputs for the clinical study report (CSR). Our team did this work in close collaboration with RedHill, and it was essential to making sure the data converted to CDISC standards from the legacy study still supported all the results that were presented in the original CSR. We documented all the discrepancies uncovered, no matter how minor they were, and carefully explained all of them in the FDA reviewer’s guide.
As part of the CDISC conversion process, Bioforum also had to map and match its standardization practices to those of the CROs that had worked with RedHill on the other, CDISC-compliant clinical trials associated with the study drug. Our team made sure general mapping assumptions were identical across all the studies included in the submission.
Beyond the CDISC conversion, Bioforum recoded the medical terms across all of the studies, creating consistency by converting all of the terms to the most recent dictionary version of the most recent clinical trial. We retroactively reprogrammed and mapped the data for the legacy trial and converted the raw datasets to SDTM/ADaM standards. In doing so, our team also created all the necessary documentation and metadata and applied the appropriate value-level mapping during the generation and validation process. Our mission was to ensure the results we prepared for the integrated summaries could be very closely compared to the results presented in the CSR of each individual trial associated with the study drug.
Even with a well-defined data standard in place, a certain amount of variability is to be expected. This is compounded if the integration includes multiple studies that are not identical in their design, as with the clinical trials associated with the Talicia® NDA. To overcome this challenge, our team of statisticians, made recommendations regarding which data would add value from an efficacy and safety perspective and, thus, should be pooled and analyzed for the ISS and ISE submission packages. Working closely with the RedHill team, Bioforum assessed all the parameters and developed and implemented a clear strategy of how best to pool – and not pool – the clinical trial data, identifying solutions that would withstand rigorous reviews, both internally and by regulatory authorities. We also ensured that the Statistical Analysis Plan reflected all of this, carefully outlining the strategy for the complex pooling process, as well as the steps taken to implement it on behalf of RedHill.
In May 2019, RedHill submitted its NDA for Talicia®. The FDA accepted the NDA for priority review two months later, in July 2019, and approved the therapy for the treatment of H. pylori in adults in November 2019. The clear, consistently formatted and thoroughly documented ISS and ISE packages Bioforum prepared contributed to a seamless regulatory review process.
We’re proud to have been part of Talicia®’s story and RedHill’s partner in this exciting journey. This successful partnership was based on close collaboration with the sponsor, all along the way. Bioforum established regular communications with RedHill, and our experienced, cross-functional project team knew what questions to ask to define clear objectives and how to manage the complexities associated with integrating the results of the different studies and coordinate ambitious timelines. Bioforum’s ability to convert the datasets and deliver the submission packages on time is another key factor that enabled RedHill’s success in preparing and submitting a successful NDA.
INDICATION AND USAGE
TALICIA is a three-drug combination of omeprazole, a proton pump inhibitor, amoxicillin, a penicillin-class antibacterial, and rifabutin, a rifamycin antibacterial, indicated for the treatment of Helicobacter pylori infection in adults.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of TALICIA and other antibacterial drugs, TALICIA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS
- Known hypersensitivity to omeprazole, amoxicillin or any other beta-lactam antibacterial drugs, rifabutin or any other rifamycin, or any component of TALICIA.
- Rilpivirine-containing products.
WARNINGS AND PRECAUTIONS
- Hypersensitivity Reactions: Serious and occasionally fatal reactions (e.g., anaphylaxis) have been reported with components of TALICIA. If hypersensitivity reactions occur, discontinue TALICIA and institute immediate therapy (e.g., anaphylaxis management).
- Clostridioides difficile-Associated Diarrhea (CDAD): Evaluate if diarrhea occurs.
- Reduction in the Efficacy of Hormonal Contraceptives: Additional non-hormonal highly effective methods of contraception should be used while taking TALICIA.
- Acute Interstitial Nephritis (AIN): Observed in patients taking Proton Pump Inhibitors (PPIs) and penicillins. Discontinue TALICIA if AIN develops.
- Cutaneous and Systemic Lupus Erythematosus: Mostly cutaneous; new onset or exacerbation of existing disease; discontinue TALICIA and evaluate
Most common adverse reactions (≥1%) were diarrhea, headache, nausea, abdominal pain, chromaturia, rash, dyspepsia, oropharyngeal pain, vomiting, and vulvovaginal candidiasis.
Components of TALICIA have the potential for clinically important drug interactions. See full prescribing information for important drug interactions with TALICIA.
USE IN SPECIFIC POPULATIONS
- TALICIA may cause fetal harm.
- Renal Impairment: Avoid use in severe renal impairment.
- Hepatic Impairment: Avoid use.
To report SUSPECTED ADVERSE REACTIONS, contact RedHill Biopharma INC. at 1-833-ADRHILL (1-833-237-4455) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Please also see full Prescribing Information.