CROS NT looks at the regulatory requirements from both the EMA and FDA with regards to Integrated Summaries of Safety & Efficacy and how to successfully prepare these analyses from a statistical and documentation point of view.
Integrated Summaries of Safety and Efficacy are not only required for New Drug Applications, they are considered some of the most important documents for submissions. They are not simply summaries, but rather they are analyses of results that determine the safety and effectiveness of drugs in development, including rare adverse events (AE). ISS and ISE analyses also play an integral part in the CTD/eCTD. Therefore, the biometrics team – from Statistician to Medical Writer – needs to work together and communicate effectively in the preparation of Integrated Summaries.
The FDA requires both ISS and ISE submissions for New Drug Applications. Within the CTD, this includes both an overview and summary of clinical efficacy and safety. Within the Clinical Study Report, submissions must contain reports of analyses of data from more than one study (including any formal integrated analyses, meta-analyses and bridging analyses).
At the end of 2015, the FDA finalized guidance on Integrated Summaries of Effectiveness for NDAs and BLAs. The FDA officially defines ISE as a “comprehensive integrated analysis of the effectiveness of a study drug”. The guidance released in 2015 differentiates ISE from the Summary of Clinical Efficacy stating that ISE should be a “self-contained, detailed analysis that comprehensively examines relevant data from multiple sources intented to provide the substantial evidence of effectiveness for a given drug, and describes additional information related to the effectiveness, such as dose-response, effects in population subsets, or timing or response”. The ISE is meant to provide a clear understanding of responses across studies.
Meanwhile, the EMA also requires both ISS and ISE for New Drug Applications in the European Union and has specific questions that must go into the CTD regarding clinical overview and summary and integrated summary. EMA submissions include statistical analyses of safety data and meta-analyses of efficacy data and require expert medical writing.
ICH guidelines for eCTD submissions (supported by both the EMA and FDA) prefer the use of CDISC standards, particularly SDTM and ADaM.
The requirements laid out by the regulatory authorities make collaboration between biostatisticians and medical writers inevitable. The challenge is understanding what roles they play in the planning and preparation of integrated summaries and the best way of collaborating.
Statisticians and Statistical Programmers
Statisticians need to be involved in the planning stages of integrated summaries. Ideally, statisticians should attend pre-submission meetings with regulatory authorities to discuss the statistical analysis aspects of the integrated summary including sample size and trial design.
From a statistical perspective, the statisticians produce a statistical analysis plan while the programmers focus on integrated datasets. The statistical analysis plan includes an analysis of aggregated data and an explanation of the methodology chosen. The biostatistician needs to highlight any inconsistencies or limitations in the sample size. In the meantime, statistical programmers pool datasets from all relevant studies. The best way to get full value from an integrated summary is to have the methdological biostatistician involved in all phases of an integrated summary life cycle.
Biostatisticians and statistical programmers collaborate to select the data to be pooled and ensure correct data formatting.
The Medical Writer ties the pooled datasets and analyses together into the final Clinical Study Report. Logically, if data is centralized and integrated, this makes writing easier. Medical Writers should work closely with biostatisticians in attendance at pre-submission meetings to understand what is expected of regulatory authorities. In terms of document structure, the EMA and FDA both have guidance on what should be included in the CSR in terms of length and content. Medical Writers need to be familiar with “Module 2” of the CTD – “the CTD Clinical Overview and Summary in Module 2 will not usually contain the level of detail expected for an ISS (…) if, the requirements of 21 CFR 314.50 can be met for a particular application by what is in the CTD Module 2 summary, then the CTD Module 2 section would fulfill the need for an ISS/ISE”.
Centralizing clinical data is key to successful Integrated Summaries preparation
Biostatisticians, Statistical Programmers and Medical Writers should be working together on Integrated Summaries from the beginning. While the biostatistician sets out an analysis plan and the programmers are pooling data, the medical writer should have a summary of analysis considerations.
Consistency is the key to ensuring Integrated Summaries are produced within budget and on time. Centralizing clinical data with one data centric vendor across a program of studies ensures data traceability, data quality and standardization. Statisticians and programmers work more efficiently when they can use previously developed programs. For example, programmers can work quicker if they do not need to rename dataset variables.
Centralizing data with a full biometrics team – including in-house biostatistician, programmer and medical writer – ensures a consistent approach to integrated summaries and surefire final product to be submitted to regulatory authorities. The dedicated team can follow a project from conception to submission, deploy the same programming macros, use the same writing style and create an ISS/ISE document template in line with company branding to be used for future summaries.
CROS NT has prepared numerous integrated summaries for both EMA and FDA submission. As a data centric CRO, we know what issues to anticipate when working with distributed data and have an excellent track record in a centralized approach to Integrated Summaries. We have statisticians, programmers and medical writers in-house with extensive experience in ISS/ISE preparation, and our biometrics teams have integrated large numbers of studies providing data mapping, warehousing, analysis, reporting and medical writing services.