CROS NT has extensive experience in planning, managing and implementing the work required for data integration when preparing integrated summaries, both for ISS/ISE and for CTD dossier submissions. Every project is unique, and our programmers and statisticians are expert at tailoring reporting requirements in order to efficiently and effectively meet the needs of the client and the regulatory authorities. CROS NT has a 100% on-time submission rate for ISS/ISE.
Integrated summaries of safety (ISS) and efficacy (ISE) are complex documents, presenting an integrated analysis of the safety and effectiveness results from all clinical trials performed on a study drug. Data from all clinical trials are pooled together and analysed as a whole, producing combined statistical results. The FDA requires ISS and ISE reports for New Drug Applications. In Europe, similar data are required for CTD-dossier submissions.
Step 1: Planning and Project Management
Effective project management, including project plan development, risk management, communication plan, resource planning and project monitoring, are essential when preparing integrated summaries. Our expert programmers and biostatisticians advise on best practices for data pooling and analysis and can recommend how time to approval can be reduced by careful up-front planning. For example, if the sponsor intends to submit to the EMA, integrated ADaM datasets are not required; which is a key consideration in the overall planning process. It is essential to understand sponsor requirements during planning in order to recommend the best strategy to use for data pooling. For example, are pooled SDTMs required? Or only pooled ADaM datasets? Flexibility is important and changes are an acknowledged part of the overall process.
If required, separate teams can be used for the safety and efficacy summaries to allow the work to be produced in parallel. The functional teams will be different, but the Project Manager will ensure a common project strategy and arrange regular meetings to ensure harmonization and no loss of efficiency.
Step 2: Gap Analysis & Data integration plan
The key to faster and more efficient preparation of integrated summaries lies in the Gap Analysis. Data sources are likely to have been prepared by different teams, different companies and at different times. This means there are inevitable variations in formats, quality, coding dictionaries and potentially missing data or documentation. A Gap Analysis is imperative in defining the scope and challenges of migration activities prior to the beginning of the integration process. The Gap Analysis involves reviewing all available documentation and data for the studies to be integrated to determine the level of effort required. The results of the Gap Analysis will form the basis of the Data Integration Plan, a detailed document that specifies which datasets need to be migrated to which standards and how all the study data will be integrated efficiently.
Step 3: Statistical Analysis Plan (SAP)
The SAP defines the statistical methodology, algorithms and mock shells to be used for presenting the integrated data, such as proportions, survival curves, and clinical significance. Other considerations include subgroup analyses, data collected differently across different trials, and grouping of studies and different treatment doses. Agreeing on the SAP, methodologies and programming formats helps to reduce the number of review cycles, ultimately saving time and costs.
The biostatistician works with the clinical team to define the grouping of studies, variables, endpoints to be presented as well as subgroup analyses (i.e. age, gender, race, country, as well as dosing ranges). Separate SAPs will be prepared for the efficacy and the safety analyses. It is also important to have the final SAP and Clinical Study Report (CSR) for each included study.
Each SAP will include a description of the studies to be integrated, algorithms and rules to be applied in order to harmonize the data across the studies and the statistical methodology to be applied. The design of the corresponding shells for the tables, listings and figures will be presented in an Appendix.
For the safety summary, the focus will include analysis of adverse events, serious adverse events, adverse events of special interest, laboratory parameters, concomitant medications, as well as other relevant parameters (e.g., ECGs, vital signs). The integrated efficacy summary will include analysis of the main efficacy endpoints and the SAP will include details to explain the methodology utilized to combine the results of the individual studies, as well as any specific data handling rules.
Step 4: Data Migration and Data Integration
The Data Integration Plan and the SAP guide the migration process from legacy datasets to the required standards. The in-house CDISC experts at CROS NT have a wealth of experience converting legacy data to CDISC standards using bespoke SAS macros and proven programming processes. When all datasets are migrated to the same consistent standard, data integration can begin according to the data integration plan. There are several factors which can influence the complexity of the data integration process. These include:
- Similarity of the studies in terms of design, dose, duration and indication
- Year in which the studies were conducted
- Current state of the data and documentation
- Type of analysis required and the analysis variables
- Indication and phase of the studies
- Language: data may need to be translated before it can be used
Integrated datasets should be validated, CROS NT uses independent programming to ensure the quality and correctness of the datasets, including external validation of adherence to CDISC standards using Pinnacle 21.
Step 5: Analysis and Reporting
Using the integrated datasets, tables, figures and listings (TFLs) are created according to the requirements of the SAP. CROS NT has a suite of in-house macros to expedite the production and validation of TFLs to reduce project time and costs. The TFLs are reviewed by a biostatistician and can also be compared to the original CSR outputs for each individual study in order to ensure consistency across the project. Our team of experienced medical writers use the most up-to date templates and regulatory guidance to create the final integrated summary documents. All documents undergo independent quality control (QC) review to ensure consistency and accuracy throughout.
Consider Common Challenges
- Communication: effective management of the cross-functional team, ensure timely responses to questions
- Budget and Costs: costs are dependent upon the complexity of the studies and the format and consistency of the data
- Operational: diversity of study data and presence of documentation, data harmonisation process can be complex
- Timelines: no flexibility as submission dates are usually fixed, ability to adapt and respond rapidly to change.
The experienced programming and biostatistics team at CROS NT can undertake effective data integration, harmonisation and analysis processes to efficiently and effectively meet the needs of global clients and regulatory authorities. For more information about our capabilities in preparing integrated summaries for ISS/ISE and for CTD dossier submissions please click here.