Costs associated with integrated summaries of efficacy and safety (ISS/ISE) can be burdensome for some Sponsor budgets – with increases arising from all sorts of factors from consistency issues to meeting tight timelines.
How can these costs be reduced and timelines maintained?
The key to faster and more efficient preparation of ISS/ISE lies in the evaluation or gap analysis of the datasets and documentation that need to be included. These datasets are likely to have been prepared by different teams, different companies and at different times. This means there are inevitably variations in formats, quality, coding dictionaries etc. Sometimes there are entire datasets missing that need to be found. It’s important to find out if there is a full specification available on all of the studies (SAP, eCRF, dataset specifications, CSR, etc.). Also, the programming team needs to determine the level of similarity in the datasets for the individual studies.
Full consideration must be given to what studies or populations are needed to adequately support the proposed label. Statisticians should outline the specific issues that the integrated summary will need to cover and identify the key safety parameters that will need to be part of an ISS based on the pivotal studies and special populations. Essentially, it is a case of identifying what data was collected in what studies, what populations are present, and in what time schedule was the data collected. The statistician(s) should work with the Sponsor to determine how the pooled data will be used for data mining to ensure that the final mapping provides data in an optimum format.
It is essential for an experienced project manager (preferably with a programming background) and senior programmers, statisticians and medical writers to give the necessary time to thoroughly evaluate the data available. A full gap analysis is the first deliverable to the sponsor and only then can a project plan and cost proposal be confirmed.
There should be a very clear communication plan, risk assessment plan and contingency plan written and agreed before commencing the project.
It is very important that enough time and resource is scheduled for the integrated summary. Otherwise a panic situation can ensue leading to a CRO or Sponsor team having to deploy a greater number of resources to meet the timelines. This can result in higher costs and less efficiency.
A dedicated and experienced team in integrated summaries should be assigned because complexity is certain, timelines are generally aggressive and quality is a must. Also a significant budget will be allocated with executive management among the stakeholders.
Having data management, statistics, programming and medical writing services under the same roof will help with the overall planning, coordination and review. If outsourced, efficient collaboration between CRO and Sponsor will be a key factor of success. The Sponsor can help by liaising with the integrated summaries team in advance to provide an overall clinical guide so that the team can understand what the Sponsor wants to present to the regulatory authority. The Sponsor and CRO should develop a checklist of information needed such as protocols, SAPs, annotated CRFs, coding dictionaries, define.xml etc. It’s important to ensure that the most recent templates and regulatory guidelines are consulted and used throughout the project lifecycle.
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.
Agreeing on a statistical analysis plan, methodologies and programming formats can reduce the number of reviews, therefore saving time and costs. Each submission will be subjected to specific questions on statistical methodology, safety and clinical aspects. The statistician must be involved and communicate with the rest of the study team. A close working relationship between programmers, statistician and medical writer is important. Having a statistician that is also experienced in medical writing will help with the submission of clear, concise and accurate documentation. It is also vital to use a medical writer who is already very familiar with the requirements, template and guidelines needed for the final document to be acceptable to the regulatory authority.
Consistency is the key in ensuring that integrated summary preparation goes as smoothly as possible, so clear agreement on statistical methodology, data formats and coding dictionaries is paramount. Since integrated summaries provide statistical evidence based on consolidated data to support an analysis of the benefits and risks of a drug in development, the methodological biostatistician and the medical writer should be involved at every step.
Finally, it is in the best interest of a Sponsor to focus on the quality of integrated summaries since this will have a favourable impact on the review by authorities and, as consequence, on when the product is introduced to the market. A proper gap analysis and good planning will help a lot in this regard. With all this in place you can look forward to a project that will stay under control in terms of budget and delivery timelines.
As a data-driven CRO, CROS NT has particular expertise in the preparation of Integrated Summaries of Safety and Efficacy. We can support Sponsors with:
- Regulatory consultancy on EMA and FDA submission requirements
- Statistical Analysis Plan with an analysis of aggregated data and methodology
- Programming macros and pooled datasets in CDISC format
- Expert medical writing services
- Experienced project management
- High quality deliverables