Setting and adhering to a timeline for planning, drafting, reviewing, and editing regulatory documents needed for the submission dossier is a major challenge for drug development teams. I think of this process as having three phases: “discovery, drive, and survive.” In a previous blog post, I discussed the planning that occurs in the discovery phase. In this blog, I’ll discuss common planning pitfalls and how to avoid them.
- Not knowing what “done” looks like: The experience gained by having been through the entire submission process from development through to defense, approval, and lifecycle management is invaluable. When you’re starting a new submission, identify which (if any) team members know what “done” looks like because these individuals will know potential difficulties to watch out for. Ideally, you have an experienced team. If you have a very inexperienced team, look for someone internal or external to your organization who has that experience and can help guide your team through these challenges.
- Scheduling summary document preparation in parallel with source document preparation: This pitfall refers to teams attempting to draft and review either non-clinical or clinical summaries in parallel with the supporting study reports. Trying to keep consistent messaging across documents that are undergoing simultaneous revision is difficult. Although this can be done, it’s painful for everyone because this practice creates considerable rework and inefficiency. You’ll find it much more efficient for the team to have separated source document prep from summary document prep—and you’ll end up with a higher quality final submission with less stress. This is true even if it means shorter review or revision periods for those documents.
- Missing input from key stakeholders: Solicit input from all key groups involved in your submission. Your core team may be limited to representatives from a handful of functions. But you want to include all stakeholders― drug metabolism & pharmacokinetics (DMPK), publishing, and quality assurance. If key people are sitting on the sidelines, try to engage them.
- Messaging “cottage industry:” Creating messaging, such as a target product profile, is essential in drug development. However, be careful that you’re developing wording that can be inserted into the summary documents rather than messages created specifically for separate messaging documents. Such wording may not work in submission documents and require that it be reworked to use it in the submission.
- Ignoring dependencies: Make sure that you’re addressing dependencies. For example, you can’t draft an integrated summary of safety (ISS) until you have the integrated pooled safety output. And that typically depends on getting to database lock on the last phase three study. Account for the time required to get from each submission development step to the next.
- Planning for weekend and holiday work: Don’t plan your submission development schedule so that it requires weekend and holiday work. Maintain weekends as weekends and holidays as holidays. Build your schedule so it doesn’t require that work. If you build a schedule that requires weekend/holiday work, then that’s what will happen.
Creating a detailed timeline
I use Microsoft Excel to create an easy-to view-timeline spreadsheet. The timeline depicted is organized by the following columns, going from left to right:
- Dates: Each block of five days represents the work week
- Holidays, vacation or other commitments
- Events or meetings: Identify when the team needs to be available for external events
- Document deliverables: These are color-coded for each step in the process including drafting, reviews, comment resolution meetings (CRMs), and revisions
By creating a detailed timeline, you can see whether your reviews are staggered or whether they overlap. Or if you have three comment resolution meetings scheduled at the same time. It also helps you identify dependencies so you can make them clear to the team.
Ideally, I will develop the timeline for all documents at least six to nine months before the submission’s due date. Once agreed, I also book reviews and comment resolution meetings in people’s calendars.
The Drive phase
The next and longest phase in preparing a submission is the drive phase. The key here is to maintain your purpose and drive to the submission date. Keep a sense of urgency during this stage. You want to reinforce and build upon the agreements reached upfront. Stick to your timeline and don’t let things slip “because there’s still time.” It’s easy to let a review slip one week at this point because it won’t impact your submission. But it sets a bad precedent for when you don’t have that option of delaying an activity.
During the drive phase, you develop your team’s trust with delivery. When the team completes those first few scheduled reviews, comment resolution meetings, other activities and meets their deadlines, their confidence grows. Having this strong team rapport will be valuable during the more stressful, hectic end of the submission.
Anticipate delays and flaws in the data. You can do that by meeting regularly and documenting the meeting minutes and actions. Don’t let outstanding questions linger! The sooner you address them, the better. While meetings are a good way to keep everyone updated, you will also need additional communications between meetings.
If you’ve ever done a “lessons learned” on a submission, communication was probably identified as an area for improvement. Maybe the communication needed to be more frequent, clear, or widespread. I don’t think it’s possible to over-communicate on a large submission project. It’s more important for everyone to know what’s going on than to try to limit awareness of problems. The team must be onboard and know where things stand with the submission at all times.
The Survive phase
I call the final phase of a submission the “survive phase.” This stage occurs near the end of the project, often right as you need the first document approvals. Every submission reaches a point where things are just going wrong! Submission leaders have to adjust and help show the team the path to success. Provide or find extra support where it’s needed.
What happens if you’ve been following a detailed timeline, and then a problem arises and database lock has to slip a week? Don’t panic. You have an agreed timeline, so don’t change anything that doesn’t have to change.
An advantage of developing a detailed timeline is that it facilitates visualizing your options. Maybe you can cut some documents’ drafting time if the tables are also delayed by a week. Or perhaps the statistical group can deliver the tables a little earlier. Maybe the team can shave a few days off a study report’s review. The inevitable delay arising doesn’t need to disrupt the whole timeline. Being able to see the entire submission timeline allows you to minimize the tweaks needed to address issues that arise.
Often, teams find discussing and arriving at an agreement in tough situations difficult. Staying quiet when everyone seems to be working well together is a tempting choice. But team leads who foresee looming problems must address and resolve them because otherwise the submission (and the team) will falter.
“Simultaneous” global submissions
The plan for creating submissions for different health authorities should be baked into your detailed timelines. Discuss how to manage different global submissions at the kickoff meeting, not when you complete the first submission!
Sponsors commonly submit applications for regulatory approval in multiple geographic regions. Pulling this off requires heeding several considerations. Where are you planning to submit the marketing application? In how many different regions or countries? Which ones and when? Filing a submission in the US and Europe simultaneously poses different issues for the team than submitting to the FDA first and then three months later to Europe. This is because you start running into issues of cutoff dates for ongoing studies, changes in safety reporting, etc.
Submitting marketing applications to multiple countries frequently means altering how you write regulatory documents. The indications may have to be changed because of differences in standard of care or wording that the regulatory authority has for that indication. Likewise, the dosage form or dosing strategy may differ between regions. There is also variability in risk management requirements, especially between the US and Europe. Lastly, the disease description may vary in different regions of the world.
Take home messages
All submissions have discovery, drive, and survive phases. In the discovery phase, do your homework! Ask questions to dig into the strengths and weaknesses of the program, its history, submission process aspects, the drug, and disease and indication. Have your submission kickoff 9 to 18 months before the submission date, and create detailed plans that you then make transparent to the team.
During the drive phase, keep meeting regularly with the team, document minutes from those meetings, and follow up on those actions. These habits will help you hold team members accountable. Communicate relentlessly to keep everybody informed.
In the survive phase, submission leaders should be the “calm in the storm.” Don’t be afraid to speak up, especially when the worst happens, to help drive the team forward.
Many pharma companies put emphasis on “lessons learned” after a submission is completed. Ideally, you will gather these on an ongoing basis and then finalize them immediately after the submission is complete. Document any recommendations that the team would make for future submission teams. To maximize the benefit of lessons learned, a team member should present them at the kickoff meeting for the next submission. If the next project has an inexperienced team, having someone present the lessons learned from the last submission will help them have a good start.
By following these recommendation, you are more likely to develop your submission on time without losing all your holidays and weekends. To learn more about best practices for submission development, please watch my webinar. Let me know what you think in the comments!