Advice for Sponsors New to eCTD
I often work with the Regulatory Operations department at Cato Research and I’m always impressed by the depth and breadth of their knowledge. Cato creates submissions for such a wide cross-section of the sponsor community that their associates have truly “seen it all”, and they can cite a precedent and define a best practice in response to almost any question they are asked. Recently, I took advantage of an opportunity to interview Evan Richardson, Cato’s Director of Regulatory Operations, about how he works with sponsors new to the eCTD and what advice he would offer sponsors planning to make the switch anytime soon.
Kathie: When Cato takes on creation of an eCTD submission for a sponsor who is new to eCTD, what are some of the most common questions you are asked?
Evan: The two of the most common questions are related to timelines and authoring best practices.
Especially when we’re talking about larger submissions, like an IND or NDA, sponsors always want to know how fast we can make it happen. Fortunately, the eCTD format can allow for shorter timelines than sponsors may be used to from paper submissions. The time needed to print hundreds of volumes is eliminated, and the modular nature of the eCTD means that we can compile it as a “rolling submission,” module by module as documents become available. Recently, we compiled and submitted a full NDA in just two months starting from the receipt of the first document.
Also, most sponsors are now familiar with the CTD structure; however, they’re often unfamiliar with writing for eCTD submissions. They need guidance on how to create internal hyperlinks in a Word document or how to properly reference other documents for external hyper linking. We recently hosted a webinar on authoring best practices for eCTD submissions, and we routinely include such training as part of our project kickoff activities with new sponsors.
Kathie: What could the sponsor have done before contracting with Cato to improve quality and decrease rework and other work effort?
Evan: The most labor intensive part of any eCTD submission is the time spent on document preparation. This includes checking and setting the page size and initial page view, creating bookmarks, and creating internal hyperlinks. For some small documents, this can take just a couple of minutes, while it can take hours for larger (or scanned) documents. The biggest thing a sponsor can do to decrease the work effort required for a submission is to provide eCTD-ready documents, i.e. PDF documents that are already formatted, bookmarked, and hyperlinked to (at a minimum) the standards set out in the FDA guidance.
Kathie: In your opinion, if a sponsor is considering submitting in eCTD format in a year’s time, what are the most important steps they should take now?
Evan: There are many important steps that a sponsor should be taking. However, from the Regulatory Operations viewpoint, there are two things they should do that work together towards the common goal of providing eCTD-ready documents.
First, providing training early on for all document authors on the best practices for electronic submissions authoring is vital. There are so many little things, like using “Tables 1, 2, and 3” instead of “Tables 1-3,” that require little or no extra effort for an author, but can result in significant time savings in the compilation phase. Also, if all of the authors are working from the same playbook, the sponsor will have consistency from one document to the next. This will really help Regulatory Operations in the creation of external hyperlinks. It’s also a really important step in making the entire application easier to read for FDA reviewers.
Second, sponsors should require vendors, such as contract medical writers, laboratories, and CROs, to provide eCTD-ready documents. I recommend including this as a requirement in your contracts with vendors. By requiring this up front, you ensure that you will not have to spend the time and money to bring these documents up to standard during the submission compilation process.
Kathie: What eCTD-related issues require the most dialog between you and the sponsor?
Evan: We’ve been doing eCTD submissions since 2005, and we’ve seen plenty of examples of how a lack of granularity in the original application has complicated lifecycle management. With sponsors who are new to eCTD, it can be difficult to get them to see beyond the current sequence and anticipate future updates and changes to their applications. So, we spend a lot of time educating our sponsors on the benefits of increased granularity.
We also spend a lot of time educating our sponsors on the differences between the Append, Replace, and New operators and how best to use each of them. In the paper submissions world, most amendments or supplements are essentially an Append operation and many authors are often most comfortable writing in this manner. We strive to make every eCTD application reviewer-friendly, and so in the submission planning phase, we often work to help our sponsors see the benefits of revising and Replacing documents rather than just Appending new information to a previously submitted document.
Kathie: What percentage of the documents you receive from sponsors are “eCTD-ready”? What are the most common changes you have to make to prepare the documents for submission?
Even: I’d estimate that only about 10% of the documents we receive are truly eCTD-ready, meaning that they require no additional work by our specialists before they can be dropped into a submission. About 60-70% of the documents we receive are partially eCTD-ready. These documents are often partially bookmarked and/or internally hyperlinked and require moderate effort to get them fully eCTD-ready. The remaining 20-30% of documents require us to start from scratch to get them eCTD-ready.
The most common change we have to make is to set the initial view properties to the correct layout and magnification settings – about 90% of all documents we receive require this.
Kathie: I know that Cato provides 100% QC of bookmarks and hyperlinks. Do your sponsors spend a lot of time addressing navigation issues that you find, or are your Cato eSubmission teams able to resolve those issues themselves?
Evan: One of the things we do best is to integrate ourselves with our sponsors, so that we’re not just a vendor, but a part of their team. We work with our sponsors to head off potential issues early on, so that we don’t find ourselves in a position where we are uncovering major navigation issues during the QC process. As a result, the overwhelming majority of issues identified during the QC process are minor things like misspelled bookmarks or bookmarks and hyperlinks that are nonfunctional or point to an incorrect destination. Our sponsors typically rely on our project teams to resolve these issues. We’ve found that educating our sponsors on eCTD best practices from the very beginning is the best way to minimize problems throughout the duration of the project.
Kathie: How do your sponsors review their eCTD sequences? Do you provide training on what they should be looking for in a review process?
Evan: We always recommend that our sponsors use GlobalSubmit REVIEW to review their eCTD sequences. The ability to view your submission exactly as the FDA reviewers will see it makes REVIEW a great tool for the QC process. For large submissions like a NDA, we encourage our sponsors to visit our office to review the submission in REVIEW and meet with our submissions specialists. This allows us to train our sponsors on what and how to review (if necessary), answer questions, and talk through any issues that arise, all face-to-face.
We tailor the training we provide to the needs of each sponsor. For sponsors new to eCTD, we can provide the same training that our in-house QC reviewers receive. Other sponsors have their own established procedures, and don’t require any additional training from our team.
Kathie: Cato often helps small Pharma with their eCTDs with the long-term plan that these sponsors will eventually become self-sufficient and take their publishing process in-house. How do you these sponsors to learn and gain experience so they will be well-positioned to make this move?
Evan: Any eCTD vendor can take your documents, plug them into the eCTD structure, and send you back a compiled submission, even if it sometimes means forcing a square peg into a round hole. Our goal is to be more than just a vendor; we want to be your partner. In addition to providing you with the technical capabilities to compile and submit eCTD sequences, we provide you with the wealth of knowledge and experience we’ve gained since our first eCTD submission in 2005. Our project teams integrate with a sponsor to provide advice and training from day one on the best practices for eCTD submissions. Over the years, we’ve had several sponsors transition to in-house publishing systems, and we take pride in knowing that these sponsors have built their own publishing capabilities upon the foundation of knowledge, skills, and experience that Cato Research provided.
Evan Richardson is the Director of Regulatory Operations for Cato Research, a full service, international CRO. He contributes frequently to Cato’s blog, Ask Cato. You can reach Evan by email at firstname.lastname@example.org or by phone at 919-361-2286.