Editor’s Note: Successful adoption of the eCTD involves the strategic assimilation of the right people and the right technology. It requires a clear understanding of the processes and best practices that ensure success. To provide some key insights into eCTD publishing, we asked Evan Richardson, Associate Director of Regulatory Operations, Cato Research to author today’s guest post.
For several years, experts from both industry and FDA have extolled the virtues of eCTD submissions. The message is clearly sinking in; FDA reports that almost 70% of new NDAs and 41% of new INDs are now submitted in eCTD format. There are obviously many benefits to switching from paper to eCTD submissions, but how do you take advantage of them if you’ve already filed your application in paper?
Fortunately, it’s relatively simple to convert your application from paper to eCTD. I’ll use an IND as an example in my explanation below, but the process applies to NDAs or BLAs as well.
Step 1: Check-In with Your FDA Regulatory Project Manager
Before beginning the conversion process, I recommend that you call your assigned Regulatory Project Manager (RPM) at FDA and let him or her know what you’re planning. A close and cordial working relationship with your RPM can be an invaluable asset, and I think it’s always a good idea to keep him/her apprised of any major submissions on the horizon. Almost certainly, your RPM will be very pleased to hear that you plan to convert to eCTD and will offer their blessing on the endeavor. Each FDA review division seems to have its own quirks, so you should also be sure to ask if there are any special concerns that you should keep in mind, just in case.
Step 2: File Your Last Paper Submission
You’ll file one last paper submission to your IND. This general coorespondence submission will consist of only a cover letter and a Form FDA 1571. In the cover letter, you should include a statement similar to the following:
The purpose of this submission is to notify the Division of [Sponsor]’s intention to submit all future submissions to IND xxxxxx in eCTD format through the Electronic Submissions Gateway (ESG). Currently, IND xxxxxx is submitted in paper format; henceforth, all submissions to IND xxxxxx will be in eCTD format (beginning with SN 0000 yyyy).
(Note the reference to “SN 0000” in the last sentence. I’ll discuss this further later on.)
Step 3: File Your First eCTD Submission
At this stage, I’m assuming that you are already technically prepared to compile and submit eCTD submissions. This means that you’re working with a competent eCTD publishing vendor or that you have the necessary software and expertise in house, have an ESG account with FDA, and that you’ve made a test submission to CDER or CBER (as appropriate) to confirm that your submissions meet all applicable standards.
I recommend that you submit your first eCTD submission within three to five business days following your final paper submission. This will help ensure that the FDA has received and processed the final paper submission while still allowing you to “close the loop” and be ready for any future IND submissions in eCTD format fairly quickly.
Your first eCTD submission should also consist of only a cover letter and a Form FDA 1571. In the cover letter, you should include a statement similar to the following:
Reference is made to IND xxxxxx amendment SN yyyy, submitted in paper format on [date], notifying the Agency of the intent for all futures submissions to IND xxxxxx to be in eCTD format through the ESG. The purpose of this submission is to serve as the initial submission to IND xxxxxx in eCTD format.
According to the FDA, your cover letter should identify this submission as general correspondence; however, you should use the submission type of “Original Application” in the Regional Metadata of the eCTD, as it will serve as the anchor submission for all future submissions to the IND.
With the successfully completion of this submission, you are officially converted to eCTD!
The most frequently asked question related to the conversion from paper to eCTD is, “Are we required to resubmit everything we’ve previously submitted in paper to the ‘new’ eCTD application?” Thankfully, FDA does not require you to resubmit information that was previously submitted in paper. However, you may find it useful to occasionally “backfill” your eCTD application by resubmitting previously submitted information for the convenience of the FDA reviewers.
For example, let’s say that you plan to submit a protocol amendment as one of your first eCTD submissions, and you previously submitted the Investigator’s Brochure (IB) and the original version of the protocol in paper. When submitting the protocol amendment, you may want to resubmit the IB and original protocol just to make life easier for the FDA reviewers – they could now reference these previously submitted documents in the eCTD instead of having to request for the old paper submissions to be brought up from the archives. In this scenario, I would apply a stamp in the footer of the IB and the original protocol, marking these documents as “Previously Submitted in Paper.” I would also explicitly mention them in the cover letter, stating that they were previously submitted in paper, that they have not been changed from the versions previously submitted, and that they are now being provided in the eCTD for the convenience of the reviewer. Such a statement will allow the FDA reviewers to process your submission without the need to re-review these documents as if they were newly submitted information.
Another issue to consider is sequence numbering. According to FDA, you can start with sequence number 0000 or you can use any other sequence number. Your software should allow you to change the sequence number from the default to any number, so I recommend that you continue with the sequence numbering you’ve been using in your paper submissions. From experience, I can tell you that this will avoid the logistical complications that crop up when you restart the sequence numbering at 0000 for your first eCTD submission.
Update (October 27, 2011): Thanks to Missy Fussell of Allegro Solutions for updated information regarding sequence numbering. The post has been updated to incorporate the information she provided.