An initial marketing application submission is a major undertaking that requires a large team, numerous tools and a litany of subprocesses to work together in harmony for a successful outcome. Leaving any of this to chance is likely to result in missed timelines and excessive crunch time. With thorough planning, careful execution and the ability to navigate unexpected challenges, the odds of success can be greatly improved. This high-level walkthrough will raise important considerations when planning an electronic Common Technical Document (eCTD) submission.
Planning, Timelines and Organization
Good planning begins with a good road map. Most often this is an eCTD content plan, but it also may include Gantt charts, shared calendars or other tracking software. Regardless of the tools employed, it is critical to set target dates for each milestone at the most granular level possible. This means every document intended for the final submission should be tracked from development, authoring, content approval, submission building, document publishing, through final reviews. These target dates should be realistic and chosen with enough buffer room to withstand the inevitable unexpected delays that occur. It is important to not overlook parts of the process or make assumptions. For example, the planning document may have included review cycles, but not a specific amount of time to make any changes stemming from that review or time to verify the changes. It is essential to make these milestone dates as visible as possible. Depending on what tools have been selected, incorporating notification emails and color coding to highlight tasks with imminent due dates could be beneficial.
Effort should be made to take advantage of asynchronous timelines when building milestones. For example, the nonclinical and Chemistry, Manufacturing and Control (CMC) documents may be completed before the clinical and summary documents. Where this is the case, there is no reason to wait for the rest of the submission to be complete before beginning the review process. Reviewing and approving sections of the submission on a rolling basis as they are completed will help minimize the bottlenecking that often leads to crunch time at the end of a large submission. With certain modules already locked down, teams can focus all their attention on newly authored pieces and submission finalization. This compartmentalization is not limited to the module level either— if possible, it would be advantageous to finalize certain studies or subsections of modules as early as possible.
The review process also poses logistical questions. A thorough Quality Check (QC) of a submission the size of an initial marketing application is likely to generate a long list of issues that need addressing. Each of these issues represents its own sub-process of evaluating the issue that was raised, deciding on a path forward if it is critical enough to address, making any corrections needed and verifying those in the final submission build. Roles and responsibilities should be clearly defined so it is obvious who owns each of these steps. It may be beneficial to assign someone to triage issues so that one person has complete visibility over all the comments coming from each functional area. A centralized tracking system for issues is incredibly helpful in recording the steps and resolutions associated with each issue that is raised during QC. Often sponsors rely on individual QC spreadsheets provided to each reviewer. This can lead to disorganization and difficulty managing version control. When there are multiple reviewers working on several QC spreadsheets each, teams could end up managing dozens of spreadsheets.
If possible, use a single shared document or preferably a cloud hosted solution to record and track issues. This way, everyone can have access to the same information during QC efforts to avoid unnecessary or duplicate work.
Managing the Submission Team
Despite one’s best efforts, all plans are subject to change once they are in motion. The planning document is a living document that will need to be updated and adjusted to account for the unexpected. It is important to establish who owns the document and who is responsible its maintenance. This process should be clearly defined, and if multiple tracking solutions are being used, any changes to one need to be propagated to the others. Communication plays a key role here as changes to the timing of one milestone will likely have ripple effects on subsequent steps and the people involved with those tasks. The clinical team may not see a big issue with pushing the finalization date of a Clinical Study Report (CSR) by a week, but that may delay the authors from writing the related summaries, which in turn pushes the document publishing back and compresses the final review timeline. Ripple down effects are not always visible to the entire team. To combat this, it is important to keep everyone engaged and actively involved throughout the entire process. Authors may think their job is done once the content is approved, but questions frequently come up that require their input during document publishing and submission finalization. Content owners should expect to be responsible for their portions through final submission and continuing into the agency response period.
Cross training can be valuable as well to get people thinking about their influence in the success of other functional areas. A successful submission involves resources from regulatory affairs, regulatory operations, medical writing, IT, marketing, senior management and other areas all of which have differing types and levels of expertise. The more each group understands about what other groups are doing the higher the likelihood of developing a positive cooperative working environment. Everyone involved should have a basic understanding of the document publishing process and eCTD concepts even if they are not directly responsible for building the final submission. This training is most valuable when done in the early in your process or as part of the project kick off.
Another important question to answer when evaluating a team’s submission readiness is how much of the work will need to be outsourced. This will be dependent on the size and structure of the organization and its long-term goals. Use a content plan to assess the scope of the submission and evaluate the staff and budget to ensure the team is able to support the work.
It may be possible to grow the internal team to support all aspects of the initial filing, but if additional resources are not expected to be needed for subsequent filings, it may not be economical to do so. This is where the flexible staffing of a vendor can be an advantage. If employing vendors, it is important to evaluate and select one as early in the planning process as possible. They should be involved in the creation of the timelines and confirmation of the project scope to ensure all parties are aware of the milestones and have a plan to meet them. There are logistical hurdles to consider as well. How will content between vendor and sponsor be transferred securely? Are there any version control or archive issues if working in different systems? How does working with a vendor change the final review plan? Have these discussions in the very beginning of the planning stage and factor the outcomes into the timelines.
Once the team is established and trained, the working dynamic should be documented. Responsibility Assignment Charts (RACI) and organization charts are useful tools to ensure everyone is aware of who and what they are accountable for. They also will help to reassess whether there are any bottlenecks or issues as the project progresses.
Technology and Specifications
There are numerous technical considerations to address that can make or break a submission. The most basic of these is ensuring there is a stable IT environment for the team to produce the submission. If the team has only produced smaller presubmission and general correspondence submissions, it is important to realize that initial applications can potentially reach dozens of gigabytes in size once all the documents and datasets are included. Very rarely do organizations properly stress test their environment to ensure that the desktop environment’s performance and storage are up to the task of working with this data at a reasonable rate. What’s needed is sufficient space to store working copies of the application and the ability to transfer files fast enough to not hold up the review team as new versions of the submission build become available.
Once a basic working environment is created, assess what software is needed to complete the submission. At a minimum, an eCTD publishing tool, viewing tool and validator to produce, review and validate the submission will be needed. These can be acquired as a suite of tools from a single vendor or can be evaluated and chosen individually. A robust document management system is also important to assist with version control, approvals and storage. Cloud hosted collaboration tools can help keep track of team communications, project status and planning documents. To meet agency requirements of maintaining a validated software environment, all these tools will need to be tested and documented. This process can be more time consuming than expected due to the number of people involved and the extensive documentation requirements.
Health Authority Changes
Once implemented, it will be important to maintain eCTD publishing, viewing and validation tools as agencies can issue new technical specifications and changes that could have an impact on the tools currently being used. These updates typically come with a mandatory implementation date, so be aware of those cut offs as timelines are being developed.
Guidance updates occurring mid-stream also can be a risk. Typically, agencies provide an adoption period before they go into effect, so the regulatory team needs to be aware of what is on the horizon. For example, FDA has issued a number of changes to their data standards and requirements over the past several years encouraging sponsors to move toward their preferred formats of SDTM
. These mandates were driven by study start dates, and sponsors that did not plan to collect and present their data in the required format would have been left scrambling to remediate. Guidance documents are frequently updated with clarifying language, changes to metadata and other critical information that could impact the submission. To ensure teams stay current, it is important to monitor agency websites, work with contacts at those agencies and read industry publications.
Submission of the Initial Application and Beyond
Once the submission is produced, develop a plan to submit it to the intended agency. Depending on the region, this may be through an online gateway, physical mail/media or in person delivery. Mature eCTD regions such as the US, Canada and EU employ online gateways which offer the most convenient means of submission; however, there is still an initial setup hurdle to clear. Account creation, signature registration, test submission dispatch and any IT changes required in the system to support the gateway all take time and consideration to complete. It is also advisable to have more than one team member complete this process for redundancy. If submitting to a region where physical media must be delivered, plan for the logistics and additional time for a courier to deliver the media. In person delivery will required coordination with the agency to schedule an appointment.
So what’s next after the team has successfully made it through the early stages and planned an initial filing, authored all the content, published and built the submission and submitted on time? Response periods differ depending on the Health Authority, but regardless of the agency, be prepared to respond to questions in a timely manner. This may be at a scheduled interval such as an EMA 120/180 day submission or on the ad hoc basis that US FDA and other agencies employ. Ad hoc questions often require rapid responses, so ensure the team is ready and able to receive the feedback, develop the necessary documentation and publish the related submission on very short timelines. These submissions can range from very brief Q&A to large compilations of additional data and studies.
Once the agency’s requests have been satisfied during the initial response period, it will be time to plan for submissions relating to product approval. These will include correspondence with the agency, labeling materials and launch materials such as advertising and promotional submissions. Postmarketing requirement submissions, safety updates and other maintenance submissions continue from there. Simply put, the burden will be ongoing.
If the proper processes and planning have been established prior to the initial filing, the organization will be well prepared to meet these challenges. Unforeseen problems are inevitable in this type of work. The more thorough the plan for what to expect, the better positioned the organization will be to respond to the unexpected.
About the Author
is a regulatory operations manager at Accenture Life Sciences Solutions with nine years of experience producing INDs, NDAs, MAA, and other regulatory submissions. He can be contacted at email@example.com
McNeely R. “eCTD Submission Management.” Regulatory Focus.
August 2019. Regulatory Affairs Professionals Society.