The US NDA and EU MAA applications are complex projects that take careful strategic planning and time management. The two application types share many common elements: once one is completed, it can be repurposed to create the other. However, it is a unique challenge to build and submit both applications in the same time frame. The WAYS staff has vast experience in working within very demanding timelines and have developed 5 key tips in balancing the simultaneous publishing process.
For the purposes of this article, we will assume a standard, Centralized MAA to the EU, and an NDA submission to CDER.
Tip 1: Determine your submission date and work backwards, accounting for regional specifics
In the EU, there are pre-established Procedural Timetables, a few defined windows throughout the year when an initial Marketing application can be submitted. There may be different due dates depending on whether your product qualifies for standard review or accelerated. These timetables can be located on the EMA Website. In order to be eligible for review, a valid submission must be received by 11:59 PM Central European Time (CET) on the indicated deadline date. US NDA applications may be under internal deadlines, but the FDA does not have hard cut off dates on when an NDA can be accepted throughout the year – therefore, it is common for the European submission to drive the overall target submission date.
It is important to note: best practice is to never target the final EU deadline date as the submission date. WAYS recommend targeting at least 2 business days ahead of the deadline, to allow for any potential hiccups with transfer through the EMA gateway. It is also important to account for the time zone that you are sending from, and the time zone of the Health Authority that you are delivering to, and to strategically plan your dispatch to ensure enough time to achieve your desired stamp date. There is no rule against dispatching the US and EU submission on the same date, but it may give more peace of mind to wait for confirmation successful receipt of one marketing application before proceeding to the next.
Tip 2: Keep a detailed content plan that identifies reusable content
A clear, organized content plan is one of the most pivotal tools when it comes to a major marketing application. It may seem to be a daunting task to create a document that lists each individual component to be included in the application, but doing so allows the clearest picture on the progress of the submission and gives clarity to all parties involved on the full scope. Aside from listing documents, it is also helpful to include target delivery dates, as well as actual delivery dates. With dual applications, WAYS has found it most efficient to maintain a single content plan with tabs for the different regions, rather than trying to work between two separate plans. Anything that is being reused should be clearly marked, and then updated once finalized and present in both applications.
Tip 3: Identify rate-limiting documents early, and make a contingency plan
Inevitably, with any major projects, due dates slip, and timelines can be affected. When building an eCTD submission, this is a delicate balance, as so many documents reference each other, and therefore depend on one another to be finalized. Whether working with an internal team, or coordinating with a vendor, it is important to continuously evaluate timelines, and identify the components that can put the submission date at risk. A small, administrative document that needs little to no bookmarking and hyperlinking may be able to come in very close to the goal submission date, but a long, detailed summary document could require hundreds of links to external documents can likely not be expedited beyond a certain point.
In the case of building simultaneous submissions, time is even more constricted than usual. It is critical to finalize documents as soon as possible, in order to avoid bottlenecks in the final days leading to submission. WAYS has seen success in this case by building out the full submission and adding a “Placeholder” document for any component that is still outstanding. This way, links can be created to as many documents as possible, even if the final content is not available. However, note that the “placeholder” method will only work for links intended for the first page of a target destination. When utilizing this strategy, pay careful attention to tracking files where the method is being used – it may be helpful to temporarily put the suffix “-PLACEHOLDER” in the leaf title and remove once the final content is put in place.
Tip 4: Publish in one parent submission, duplicate finalized pieces to the other
Under a demanding timeline, it is key to maximize efficiency and avoid unnecessary re-work. For any elements that will be common across the two applications, it is best to first place them in one submission, complete publishing activities, and place the finalized content in the other once approved. There are certain elements where publishing activities will have variations across regions due to differing requirements. One prime example are Module 5 Clinical study reports. While most CSR components will be shared across the NDA and MAA, the FDA requires patient Case Report Forms to be submitted for any patients that died, withdrew, or discontinued due to a serious adverse event. These files are not required for a standard initial MAA. Therefore, in the US NDA, often the Clinical Study Report will require links to these files, which are not needed in the MAA.
In this instance, it may be tempting to publish the CSR files separately in each application. However, this approach is likely to lead to setbacks – it may be difficult to ensure that the files are published consistently, and potential issues and page replacements can slip through the cracks when trying to monitor in two locations. WAYS has found it most efficient to complete the publishing in full for one application, then duplicating to the next once finalized, and ensure that the only changes made are those necessary to conform to regional requirements.
Tip 5: Keep detailed tabs on timing: building, validation, and transfer
As the application progresses through the eCTD publishing process, the overall output will inevitably grow larger and larger in size. It is important to regularly export drafts of the submissions and run validation. This will be helpful on a few different fronts: first, it helps identify any validation warnings/errors early, and allows time for troubleshooting. Additionally, there are different validation rules for US and EU submissions, so there may be some PDFs that run clean in one application, but trigger warnings in another, and require minor alterations to be in line with the regional criteria within its specific application.
Project leads should remain well acquainted with the time it takes each application to complete an export, validate, and transfer. As the final weeks leading to submission loom closer, these factors will drive how late components can realistically be delivered in order to have enough time to generate a complete, valid product in time for the target date. Keep in mind, while our recommendation is to primarily build one submission and duplicate to the next, as previously touched on, there are some components that are required for US NDA applications that are not required for MAAs: namely, Case Report Forms and Clinical/Nonclinical Data Packages. These file types can be very large and lead to a disparity in overall submission size between the NDA and MAA. As the submission date approaches, if there are suggested last-minute changes to documents that are common across both components, the impact and timing needed to update both needs to be evaluated.
These 5 tips are just a small glimpse into the insight that the WAYS staff can offer on this type of project. Feel free to contact us with any questions, and be sure to follow WAYS on LinkedIn for continued access to our tips and insights.