eSTAR Is Born: Advice for CDRH’s New Electronic Reality

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ARTICLE SUMMARY:

Starting next October, every 510(k) sent to FDA will have to be compiled with CDRH’s eSTAR electronic template and submitted via its new online portal. Here’s a look at this big shift from the device center’s analog past and some expert tips on making the transition.

FDA’s device center is known as a relatively innovative section of the agency in many respects, but it has been a backwater in one particular area: the means by which companies can compile and transmit premarket submissions. 

Electronic templates and submission portals have been well-established for drug and biologic applications, but as recently as three years ago, device companies were still shipping massive piles of paper submissions along with an “eCopy” of the application on a CD or thumb drive to FDA headquarters. The paper requirement was finally removed in 2019, but mailing physical electronic media containing files that FDA staffers have to manually download and then map to internal review templates has remained the standard practice. 

But that’s finally changing. Progress toward a more digital CDRH future has accelerated in the past few years as a result of big IT investments by the center (which were somewhat controversial during the latest user fee negotiations with industry) and serious work on standardizing the structure of submissions. Those efforts have resulted into two new foundational platforms: 1) the CDRH Customer Collaboration Portal (CCP), which for the first time allows sponsors to forgo FedEx and send submissions directly online; and 2) the electronic Submission Template and Resource (eSTAR), an interactive PDF-based submissions form that (at least for 510(k)s and De Novos, so far) directly mirrors CDRH’s SMART template, which reviewers follow internally.  

On October 3, the center opened up CCP for anyone submitting any type of premarket submission and pre-submissions. And starting next October, eSTAR submissions via CCP will be required for 510(k)s, with mandates for other submission categories coming down the pike.

“One of my cautions is that people are going to think, ‘Oh, this is going to walk me through it. I can just do it even though I have no experience.’” 

Richelle Helman, MEDIcept

The general online-ness of it all has been a long time coming. It’s hard to find anybody who wants to keep placing CDs addressed to Silver Spring, MD, in the mail. “Moving CDRH into the 21st century where we don’t have to be mailing things is such a huge improvement,” says Jared Seehafer, CEO of Enzyme, a QMS/submissions platform and consulting company, which participated in FDA pilots of both CCP and eSTAR.

But the transition to a new submissions template in eSTAR, while clearly a move in the direction of efficiency, is not trivial. It comes with many of the potential hiccups and investments linked to any big IT upgrade and requires companies to reframe how they make a clear case for their device in an FDA submission.

The eSTAR Evolution

CDRH first launched a 510(k) pilot program with eSTAR in early 2020 after experimenting with a different electronic template. Last year, it opened up the template on a voluntary basis for anyone who wants to use it for 510(k)s and, subsequently, De Novos. The center touts the simplicity and accessibility of the template, leveraging an interactive PDF form. The template is also designed to speed premarket reviews by guiding sponsors to include the specific information and data that reviewers are looking for, organized to align with the internal review checklists.

Historically, one major culprit of avoidable premarket review delays is a submission that comes in with key pieces of information missing. CDRH has built up its “refuse to accept” (RTA) program over the past decade as a front-loaded completion check required before substantive review can begin. With eSTAR, the center is stepping back from RTA gatekeeping, relying more on the automated platform to ensure companies are checking the necessary boxes.

But eSTAR will require adjustments in how internal regulatory affairs teams, consultants, and others in the device submissions game do their job. Traditionally, a well-organized submission has a narrative flow to it; information and data can be framed and described all together as part of a single file. But while eSTAR’s interactive form guides the submitter to fill in core information, the sponsor will also need to provide further details, including testing data and correspondence, via attachments that can be bookmarked throughout the form. That requires a different approach to organizing information and making sure FDA can find what it needs.

“You have to have enough knowledge about what information still needs to be provided to FDA that can't just be shared in that template, and figure out how to use the attachments to convey the information you need,” Richelle Helman, a senior regulatory consultant with consulting firm MEDIcept, explained in an interview. Hellman is currently working on multiple 510(k)s and a De Novo submission via eSTAR.

And as with any big IT upgrade, there are also going to be some bugs and design issues to work out. The primary reason moving forward with a standard template for device submissions took so long is the diversity of products within the medical device industry makes it challenging to incorporate all the variability that might arise in submissions.

eSubmission Tips
  • Mandate: eSTAR and online Customer Collaboration Portal submissions will be required for 510(k)s starting October 1, 2023.
  • Tech requirements: Acrobat Pro for eSTAR; CCP account for online submissions.
  • Attachments: Sponsors should employ eSTAR attachments strategically to make a clear case to FDA, and minimize the number of attachments.
  • Don’t wait: Particularly for 510(k)s, there is no reason not to start using eSTAR for new submissions. Get used to it now before the mandate hits, experts say.  

There were some signs of early challenges with eSTAR use. An independent assessment of FDA’s device review program performed by contractor Booz Allen Hamilton in 2021 found that eSTAR submissions were linked to a higher rate of deficiency letters compared with the non-eSTAR cohort in FY 2020 and 2021, and to longer total decision times for the FY 2020 cohort. 

Barbara Zimmerman, deputy director of CDRH’s Office of Regulatory Programs, says the center has been paying close attention to user experiences and continually making changes to the system. “We take all the feedback we get very seriously, and we incorporate almost all of it in the eSTAR submission,” Zimmerman said during a panel session in September at the RAPS Regulatory Convergence meeting in Phoenix. “We are constantly updating it and revising it.”

Since the center opened up the platform to anybody, the volume of eSTAR submissions has been steadily rising, Zimmerman says. That has led to a broader variety of devices and regulatory issues coming through the template, and a diversity of experiences, depending on the details of the submission and the submitter’s digital competence and setup (e.g., do you have the correct software downloaded?).   

One speaker during the audience Q&A at the RAPS panel said, in her experience, eSTAR is “really not usable for complex submissions.”

But checks by Market Pathways with various sources suggest that is not necessarily the majority opinion. “I had a great experience. I love it. I had no problems with it,” notes Natalie Vollrath, another senior regulatory consultant with MEDIcept. Vollrath recently submitted a 510(k) for a client via eSTAR. Subsequently, she had to submit another 510(k), for a different client, to a review division that wasn’t yet accepting eSTAR. It was “painful” to go back to the more manual approach, she said.

Get Attached to Attachments

Still, it requires a change in mindset, particularly regarding use of the attachments. Helman, from MEDIcept, points to an example that required “a little bit of creativity” with the De Novo she is submitting.

One section of the eSTAR template asks the sponsor to identify prior submissions related to the device and requests that all correspondence tied to those submissions be attached. In this case, the company had eight or nine prior interactions with FDA, including four pre-submissions on the De Novo, “and they've changed their intended use,” Helman explains. That adds up to many disparate pages of communications that, on their own, don’t convey to a clear message. Just attaching all of the correspondence files, as prompted by the template, “is going to lead to a quagmire for whomever the reviewer is,” she notes.

“A lot of the forms are built in, like your IFU form, the 3881, and then also the CDRH Premarket Cover Sheet.”

Natalie Vollrath, mediCEPT

In a traditional submission everything would be contained in a Word document with an introduction tying it all together. So Helman attempted to simulate that approach by writing a cover letter and putting that and all of the correspondence into a single PDF attachment for that section of the template. “We have the cover story that explains everything and then says, ‘OK, on pages 15 through 20, it's this one, on pages 21 through 30, and so on.’ You walk them through it,” she says.

Generally, companies should aim to minimize the number of eSTAR attachments to make it easier for a reviewer to find what they’re looking for. If there are multiple documents that need to be included in support of a particular item, it’s best to combine them into a single file and create a table of contents, notes Vollrath. “Try if you can to keep it to one attachment,” she says. 

Sponsors also need to think about how they are referencing information in other parts of the submission to ensure it’s easy to follow. In traditional applications, it was natural to reference section numbers and page numbers, but those are gone in eSTAR. “I would recommend actually calling out the section name, [for example] if it's the device description section and whatever document is attached to that,” Vollrath says.

These seem like relatively straightforward steps to take, but the risk, Helman suggests, is that the more automated nature of eSTAR will coax people into thinking they don’t need to take extra steps to communicate and organize the information in a manner that will facilitate FDA review. “One of my cautions is that people are going to think, ‘Oh, this is going to walk me through it. I can just do it even though I have no experience.’ And I think that's going to be a problem.”

Asking Too Much?

The guided nature of eSTAR is, nonetheless, its primary benefit. FDA officials often refer to it as akin to TurboTax for device submissions. It includes green/red color-coding to mark sections that are complete and incomplete, and also for the overall completion of the application. (See Figure 1. ) FDA won’t review mailed eSTAR submissions marked incomplete and the CCP online system will kick back eSTARs deemed incomplete.

Figure 1 – eSTAR Screenshot

These features are why FDA has waived its RTA process for eSTAR submissions. Instead, the agency says it will perform virus scanning and a less-thorough “technical screening process” within the first 15 days after a submission.

The guided structure of eSTAR is also intended to facilitate more efficient reviews on FDA’s side because the information is organized specifically to align with the agency’s review template, so a reviewer is more likely to identify what they are looking for when they need it.

The flipside of greater automation, though, is less flexibility. The electronic template is unbending about what it considers incomplete. But what if it is asking for information you, as a sponsor, don’t think is appropriate for the submission at hand?

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That, in some cases, has been an issue for sponsors. For instance, during the session at this year’s RAPS meeting, a speaker relayed his company’s experience of making an eSTAR submission for an existing device that was being updated. The company ultimately had to pursue a traditional 510(k), rather than a Special 510(k), because of certain elements of the modification, but the device materials remained exactly the same. According to the speaker, eSTAR forced the firm “to go back and reenter all the biocompatibility testing that was done maybe six to seven years ago, and that might have been [completed] under another standard.” It unnecessarily left the company “open to questions about biocompatibility” even though those issues had already been addressed in prior submissions, he said.

FDA’s Zimmerman noted during the meeting that her staff was aware of that issue. “We are thinking about how to address it right now,” she said

In general, it seems there have been various examples of eSTAR versions seeking extra information in certain situations, and FDA fixing those issues as the agency found out about them. “The first generation had a couple of those issues, and then they fixed those,” Seehafer says.

The template blanks out what it deems as unnecessary sections based on a sponsor’s earlier input into the form. For instance, if you indicate you have a software-only device, the biocompatibility section will blank out. If you indicate your device doesn’t contain software at all, the cybersecurity and interoperability sections won’t seek inputs. In his experience, Seehafer says, those functions are working well.

However, where the template requires information that a sponsor doesn’t believe is appropriate, companies have options, according to Helman.

For instance, if the biocompatibility section remains active, but you don’t think you should have to submit biocomp testing, “instead of a test report, you could upload a document that is your toxicological risk assessment and say, ‘Based on this risk assessment, we don't feel that we need to do biocompatibility testing,’” she advises. “So even if you're not going to have something that [the agency] thinks is required...attach an attachment with that explanation.”

“That's where the regulatory knowledge and creativity is going to come into play,” Helman points out.

Finding Efficiencies

How significant an efficiency advantage CCP plus eSTAR provides remains to be seen. FDA has pointed to the lack of RTA review as a key, tangible early-stage benefit of using eSTAR, although veteran regulatory consultants suggest that might not be that significant in many cases. The RTA review clock is 15 days, and FDA says it will complete the technical screening process for eSTARs within 15 days before officially accepting it for review, so the timing may not be very different between submissions passing through either process.

“Once you have done one, you realize, ‘Oh my God, we just saved so much time in the publishing process.’”

Jared Seehafer, Enzyme

“If you have been doing this awhile, you shouldn’t really have something that [gets caught up in] RTA,” Seehafer says.

On the other hand, consultants who have been putting the interactive template to use affirm it clearly saves time in the actual process of compiling an application prior to submission, particularly after you gain some initial experience with the platform. “Once you have done one, you realize, ‘Oh my God, we just saved so much time in the publishing process,’” he says.

The template, for instance, incorporates all the individual forms that a submitter would have to track down individually. “A lot of the forms are built in, like your IFU form, the 3881, and then also the CDRH Premarket Cover Sheet,” notes Vollrath. “You don't have to go out and find those forms and make sure you have the latest and fill [them] out...It's all in one place.”

In addition, the template embeds key reference information. “What's really cool is, next to each box or almost every box, there's a question mark,” Helman says. “And when you click on it, there's a really good description of what FDA is expecting and/or it points you to the guidance that it's going to be referring to when it's reviewing that section.”

In addition, CCP offers the advantage of more immediate confirmation. “Electronic submissions can be received and formally acknowledged in a matter of hours, not business days,” notes Allison Komiyama, a regulatory consultant with RQM+, in a recent blog post. “Electronic filing no longer relies on processing large volumes of paper files at the FDA’s Document Control Center.”

Down the line, the promise of eSTAR is that the standardized submissions will actually speed up review times. More experience and data will be needed before that benefit can be validated. “I don’t know if I can say there is increased efficiency” on the review side, Seehafer notes. But there is more transparency and certainty, he says, particularly because CCP offers sponsors the ability to track the progress of reviews (currently only for 510(k)s.) “You can read out to your client and their management to say, ‘This is when we are going to hear back.’”

Even longer term, the vision for eSTAR is global. The template expressly aligns with a globally harmonized “table of contents” for regulatory submissions that has been established by the International Medical Device Regulators Forum (IMDRF). And it currently is set up to incorporate both US FDA and Health Canada submissions elements if a sponsor chooses. Those two agencies plan to conduct a joint piloting of eSTAR as a global submissions tool later this year.

Ready to Go?

At the moment, the tools remain voluntary. But, for 510(k)s—the most common type of submission that comes before FDA—CCP and eSTAR will be mandatory, with rare exceptions, starting next October 1.

To get started, you’ll need to purchase an Adobe Acrobat Pro license (the template won’t function properly with standard Acrobat or other PDF software), and it helps to make sure you are using the latest version of eSTAR. To make online submissions via the CCP, you need to register for a free system account.

Sponsors that already have 510(k) submissions in the works using traditional approaches certainly shouldn’t backtrack, Helman advises. “For anything that's already in process...the old way, I don't think that there's enough value-add in the refuse-to-accept portion to make it worth it for all the effort that it would take to convert it into the right attachments for eSTAR,” she explains.

But for any new submissions going forward there is no reason not to start gaining experience with the new platform,” Helman states. “Now that it's going to be mandatory, I would say any submission that you haven't started, just use eSTAR.” 

 

 

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