Integrated summary of safety

Study background:

PHASTAR was contracted to assist a pharmaceutical company with the conversion of 16 Legacy studies to SDTM (2 SDTM “Like” phase II studies, 14 Legacy Phase I studies) and with the pooling and reporting activities of their Integrated Summary of Safety (ISS) for a regulatory submission.

PHASTAR were supplied with legacy datasets of the 16 Phase I/II studies, Raw CRF, protocol and CSRs, alongside ISS SAP and Shells.

Legacy study data conversion:

Prior to commencing CDISC conversion, PHASTAR worked on a thorough due diligence activity, checking each study protocol and the original study data (sent in different files formats). PHASTAR created the individual SDTM specifications for each study, using their own automation tool for the RAW to SDTM mapping. The automation of SDTM annotated CRFs were also generated before any programming activities started.

During the mapping phase, the team noted that there were a high volume of inconsistencies between the CRFs provided and the raw datasets given and therefore a full reconciliation process was carried out between the available raw data and CRF pages to identify missing documentation and data. The PHASTAR team took a proactive approach to provide the specific details of what documentation should accompany the provided data and which CRF fields did not have corresponding raw data associated.

The team also reconstructed format catalogues during the SDTM mapping using the CRF options provided. During this process, irregularities were noted, investigated and reported to the sponsor (additional categorical data that the CRF didn’t account for) and provided full documentation of the handling in the SDTM Reviewer’s Guide.

Several raw datasets were also provided for questionnaire responses with no accompanying questionnaire documentation for mapping to SDTM or annotation. The PHASTAR team identified the version of specific questionnaires that were missing and sourced them from online investigation where possible.

After the 16 study SDTMs were created, the team identified key endpoints and corresponding legacy outputs that summarised the data and performed outputs reconciliation using the newly created SDTM datasets and cross-checked them against legacy reporting. Discrepancies were identified, documented, and reported to the sponsor for investigation and risk assessment. The sponsor created an addendum to the original CSR for some of the studies, explaining the issues.

The conversion of the 16 Legacy studies was finalised by the creation of Define.xml for each individual study.

ISS activities:

The ISS SAP and shells were provided by the sponsor. PHASTAR completed the integration of the pooled database using the newly created SDTM for 10 studies. During the pooled SDTM process, several critical study RAW data entry errors were observed and so programmatic solutions were implemented to identify issues:

Few subjects entered more than one study within the ISS.

PHASTAR generated an algorithm to extract demography data from each study and to look for suspected cases. This was then provided to the sponsor for their review so that documentation to support the suggested link could be identified and provided.

Subjects who moved from “parent” studies to extension study were identified and subject identifiers were updated to ensure a single identifier was used for each unique subject across the ISS.

PHASTAR created a custom demography domain to ensure that no subject level data was lost and full traceability existed to identify links between subject data.

Different controlled terminology used across all the studies in the ISS:

Studies often had very different controlled terminology due to the time they were set up and therefore CRF and RAW database design were different.

PHASTAR reviewed all studies and agreed on a single version of controlled terminology to be used across the ISS programme.

Electronic lab data was recorded with reference ranges reversed.

The PHASTAR team identified the lab data issues during data integrity checks and reported this to the sponsor with a proposed solution.

Data was noted to have been recorded using the wrong units and so during standardisation, they were identified as extreme outliers.

MedDRA version of AE domains was significantly different.

The PHASTAR team had to “up-version” legacy coded AEs by merging the data with the latest MedDRA dictionary, followed by a review from the PHASTAR management team. For studies with missing AE coding, PHASTAR’s data management team recoded terms to the latest MedDRA dictionary version.

After resolving those issue during the pooling of SDTMs, pooled ADaMs were created as well as ISS outputs (summaries and graphs). Demographics, exposure and safety (including Adverse Events, laboratory, vital signs) were created for different populations and further outputs reconciliation were conducted. PHASTAR also created the define.xml for the pooled SDTM and ADaM database.