Did you miss these important 2019 FDA medical device guidance documents?

This Regulatory Alert discusses:

  • The most impactful FDA CDRH guidance documents issued in 2019 including the 5 issued related to the 510(k) Program and the 5 issued, for digital health. We also cover new guidance documents for the De Novo Program, Q-Subs, 513(g) requests, Patient Engagement, Annual Reporting, the Safer Technologies Program, and changes to eCopy submissions.
  • Ten things you can do to speed along your 510(k), PMA, or De Novo submission.
  • An age-old question: Is FDA guidance binding?—i.e., does it have to be followed?

What were the Top 3 most impactful CDRH guidances to be issued in 2019?

1. The group of five 510(k) guidances issued in September 2019.

We are loathed to give you a big reading assignment, but #1 on our list is not just one guidance—it’s the group of new 510(k) guidances. If you have a 510(k)-cleared product on the market or plan to submit a 510(k) in the future, then you should familiarize yourself with the five new guidance documents FDA released in September 2019 intended to modernize and clarify expectations related to the 510(k) program. See below for details on each guidance.

The Abbreviated 510(k) Program guidance document, which was issued on September 13, 2019, outlines the optional submission approach for manufacturers to use to demonstrate substantial equivalence while preserving resources and efforts for all parties.

The Abbreviated 510(k) process intends to clarify Agency expectations to facilitate a more streamlined submission and review process. An Abbreviated 510(k) may be appropriate when a submission relies on one or more of the following:

  • FDA guidance document(s);
  • Demonstration of compliance with special controls for the device type, either in a device-specific classification regulation or a special controls guidance document; and/or
  • Voluntary consensus standard(s).

Manufacturers looking to utilize the Abbreviated 510(k) submission approach must submit summary reports describing the testing that was completed in accordance with applicable guidance document(s) and/or voluntary consensus standard(s). FDA provides an appendix with a list of the content to be included in a summary report. Abbreviated 510(k)s will be reviewed pursuant to the standard 90-day review period for 510(k)s.

If you are submitting an Abbreviated 510(k), be sure to check out FDA’s new Refuse to Accept Policy for 510(k)s, which includes the Acceptance Checklist for Abbreviated 510(k)s in Appendix B.

A Special 510(k) submission approach may be available for manufacturers making certain changes to medical devices that are already on the market. The review timeline for Special 510(k)s is shorter (30 days vs. 90 days), so this pathway can be beneficial for manufacturers if proposed change(s) meet the criteria in the guidance document.

The Special 510(k) Program guidance document, which was issued on September 13, 2019, provides FDA’s current thinking on the Special 510(k) program, which now includes certain labeling and design changes that are appropriate for this optional submission pathway.

The guidance document contains flow charts and examples to help manufacturers determine whether a device change may qualify as a Special 510(k). According to the guidance, a Special 510(k) may be appropriate when:

  • A proposed change is submitted by the manufacturer legally authorized to market the existing device;
  • Performance data are unnecessary, or if performance data are necessary, well-established methods are available to evaluate the change; and
  • All performance data necessary to support substantial equivalence (SE) can be reviewed in a summary or risk analysis format.

If you are submitting a Special 510(k), be sure to check out FDA’s new Refuse to Accept Policy for 510(k)s, which includes the Acceptance Checklist for Special 510(k)s in Appendix C.

FDA conducts an initial acceptance review of all 510(k) submissions within 15 calendar days of receipt. The acceptance review assesses whether the submission meets a minimum threshold of acceptability in terms of format, content, and administrative information. FDA will not waste time reviewing a submission that is administratively incomplete. If a validated eCopy has been received, user fees have been paid, and the submission passes the acceptance review, you will receive an acceptance notification and the submission moves on to the substantive review phase where FDA assesses the quality of the data and information submitted. FDA’s new Refuse to Accept Policy for 510(k)s guidance contains a checklist for FDA reviewers to use when determining whether to accept a 510(k) submission for review. This checklist should inform and instruct your submission building process. Failure to follow this guidance will likely result in submission review delays.

In addition to this Refuse to Accept Policy for 510(k)s guidance, be sure to check out the guidance documents specific to each 510(k) type, described above and below, for guidance on the substantive content.

If you plan to submit a traditional or abbreviated 510(k), you should use the 21-page Format for Traditional and Abbreviated 510(k)s guidance document that was issued on September 13, 2019 as your roadmap. This document contains critical information about how to structure your 510(k) submission, including the kind of content and data that should be submitted.

Failure to comply with this guidance often times results in delays in the submission review process, which may require you to re-submit documents, and will likely irritate the FDA reviewer(s). FDA provides an ordered list of all sections that should be included in the submission along with a detailed description of what each section should contain.

If you are submitting a Traditional or Abbreviated 510(k)s, be sure to check out FDA’s new Refuse to Accept Policy for 510(k)s, which includes the Acceptance Checklist for Traditional and Abbreviated 510(k)s in Appendices A and B, respectively.

The Safety and Performance Based Pathway guidance issued on September 20, 2019 was finalized as part of FDA’s efforts to modernize the 510(k) program. This pathway expands on the principles of the Abbreviated 510(k) program for demonstrating substantial equivalence. The guidance describes an optional pathway, the “Safety and Performance Based Pathway”, for certain well-understood device types.

When a manufacturer submits an Abbreviated 510(k), it must conform to FDA-recognized consensus standards, FDA guidance, and special controls in order to demonstrate the performance characteristics necessary to support substantial equivalence. Rather than using direct predicate comparison testing to demonstrate substantial equivalence, the Safety and Performance Based Pathway allows a manufacturer to submit robust performance characteristics necessary to support a finding of substantial equivalence for a device type.

FDA has indicated that the use of performance criteria is only appropriate when FDA has determined the following:

  • The new device has indications for use and technological characteristics that do not raise different questions of safety and effectiveness than the identified predicate;
  • The performance criteria align with the performance of one or more legally marketed devices of the same type as the new device; and
  • The new device meets all the performance criteria.

If a device cannot rely entirely on the performance criteria specified by the FDA to establish substantial equiveillance, then it is not appropriate for the Safety and Performance Based Pathway program and would be better suited for either a Traditional, Special, or Abbreviated 510(k).

2. Five Digital Health guidances issued in September 2019.

Number two on our list is another bundle of five guidances. FDA issued five guidance documents on September 27, 2019, all related to digital health content, including mobile medical applications and medical device software, to keep pace with the rapid technological advancements in the digital health space. If your current or future products include a digital health component, then you should familiarize yourself with current FDA thinking on how your product is, or is not, regulated. See below for details on each guidance.

FDA’s Policy for Device Software Functions and Mobile Medical Applications guidance supersedes the previous Mobile Medical Applications guidance that was issued in February 2015. The new guidance clarifies how FDA intends to regulate software and mobile applications. The appendices contain helpful examples of software functions that are considered medical devices, others that are not medical devices, and importantly, those that are devices but that FDA intends to exercise enforcement discretion over—meaning software functions that FDA does not intend to enforce requirements under the Food, Drug and Cosmetic (FD&C) Act.

The Medical Device Data Systems, Medical Image Storage Devices, and Medical Image Communications Devices FDA guidance document contains current Agency thinking on medical device data systems (MDDS), inter alia. Additionally, FDA defines Non-Device-MDDS and Device-MDDS and provides example of each.

The Clinical Decision Support Software draft guidance document discusses the term “clinical decision support” or “CDS” that provides information to enhance a patient’s health care. The previous version of this draft guidance attracted quite a bit of industry controversy due to its broad definition of CDS. The purpose of this updated draft guidance document is to describe a risk-based categorization that will be used by FDA to distinguish between CDS software that does meet the definition of a medical device from those that do not. This new draft guidance seems to be more acceptable to the medical device industry; however, the health care industry has recently raised concerns about the narrowed CDS interpretation, which may result in the exclusion of important software from regulation. We expect that CDS discussions will continue.

The FDA guidance Changes to Existing Medical Device Software Policies Resulting from Section 3060 of the 21st Century Cures Act provides the current FDA approach to regulating medical device software. FDA outlines four general categories of medical device software products that do not meet the definition of a medical device and includes examples for each.

The Off-The-Shelf Software Use in Medical Devices FDA guidance document contains helpful recommendations for manufacturers using Off-The-Shelf (OTS) software as a component of their medical device. Specifically, this guidance lists out the information that should be included in the premarket submission about the OTS software. You should incorporate the recommendations from this guidance document into your product development process if your medical device utilizes OTS software.

3. De Novo guidance.

CDRH’s mysterious De Novo program requirements are fleshed out in this 2019 guidance which provides checklists for what you need to include in your De Novo submission. Because this guidance lays out the “must have” and recommended elements of a De Novo request, it is indispensable for anyone submitting a De Novo. See below for details on the De Novo program and new guidance.

Medical devices that are new or novel, and thus not substantially equivalent to a previously cleared or pre-amendments device, are automatically classified as Class III—which would require FDA approval of a pre-market approval application (PMA). The De Novo classification process allows medical device manufacturers to submit a De Novo request to FDA to obtain a Class I or Class II classification. Upon receipt, FDA beings an acceptance review for administrative completeness before a substantive review is performed. FDA may Refuse To Accept (RTA) the application or delay the process if the submission is not administratively complete. This is a crucial step in the De Novo classification request process.

If the De Novo request is accepted for substantive review, then the FDA review clock start date is the day the Document Control Center received the De Novo request. If, during the acceptance review, additional information is requested or an RTA is issued, then the FDA review clock start date will be the day the Document Control Center receives the additional information that results in acceptance for substantive review. Generally, the acceptance review is completed within 15 calendar days. If the acceptance review extends beyond 15 days the request is considered to be under substantive review. Once accepted for substantive review, the calendar days used for the acceptance review (up to 15 days) are included in the calendar days to reach a final decision for the De Novo request.

De Novo requests usually take at a minimum 120 days (the statuary time frame for review) from start to finish. During the substantive review, FDA must make a classification determination for the device that is the subject of a De Novo request by writing within 120 days (roughly 4 months) of the request. However, the clock will stop if FDA issues an Additional Information (AI) letter or requests information via an interactive review. At which point the requestor has 180 days to respond to the FDA. Once the response is received the clock starts again. As a result, the process often takes longer than the 120 days. By contrast, the statutory time frame for review is 180 days for a PMA and 90 days for a 510(k).

For FDA’s 2020 fiscal year, which runs through September 30, 2020, the standard user fee for a De Novo classification request is $102,299, but $25,575 for a small business. In comparison, the standard fee for a PMA submission is $340,995, and $85,249 for a small business. See FDA’s FY 2020 User Fees for more information on user fees. See Medical Device User Fee Small Business Qualification and Certification to determine if you may be eligible for reduced user fees.

The De Novo pathway is not appropriate for all devices. For those that are on the cutting edge of science and development, the De Novo pathway may allow a manufacturer to get to market quicker and in a more cost effective manner than the PMA process which is required for Class III devices. Not only is this good news for manufacturers, but patients are able to benefit from these new products sooner.

The Acceptance Review for De Novo Classification Requests FDA guidance document is intended to provide transparency and clarity on the procedures and criteria FDA uses in assessing a request for a De Novo submission. This final guidance document supersedes the draft guidance that was issued on October 30, 2017. Differences between the draft and the final guidance include additional information about De Novo requests for combination products, statements of compliance for clinical investigations, and declarations of conformity.

Importantly, the guidance document contains a checklist for preliminary questions, acceptance review, and recommended content. These are the checklists that FDA reviewers will utilize when performing the acceptance review of a De Novo request. This is like getting a sneak peek at the other team’s play book!

This information is incredibly valuable to a manufacturer with a potential De Novo product as it allows for the submission of a more complete and accurate package to FDA. This can reduce the review and acceptance timeline as well as costs.

What new medical device guidances just missed our Top 3 list?

The following are some additional 2019 CDRH guidances that you should know about.

FDA finalized its Requests for Feedback and Meetings for Medical Device Submissions: The Q-Submission Program guidance on May 7, 2019. Although it is largely similar to the 2017 draft version, there are some minor updates. FDA added a helpful table that lays out the method and timeframe for feedback by Q-Submission type (pre-submission, submission issue request, informational meeting, and study risk determination). Discussing waiver requests under 21 CFR 812.28 (related to FDA’s acceptance of clinical trial data gathered outside the U.S.) was removed from the Q-Submission Program scope and cybersecurity was added as an appropriate Q-Submission topic.

If you are unsure of your device’s classification after reviewing FDA’s website and all applicable guidance documents, you may consider submitting a 513(g) Request for Information. FDA finalized its FDA and Industry Procedures for Section 513(g) Requests for Information under the Federal Food, Drug, and Cosmetic Act guidance on December 16, 2019. The guidance contains a nice overview of FDA’s device classification process along with helpful links/resources. In response to a 513(g) Request, FDA will generally only tell you the generic device type, device class, whether a PMA vs. 510(k) is required, and applicable requirements/guidance documents. FDA will not review data, testing plans, or identify a suitable predicate device.

Device manufacturers currently designing a clinical trial or considering conducting a clinical trial may find FDA’s new draft guidance on Patient Engagement in the Design and Conduct of Medical Device Clinical Investigations useful. FDA acknowledges that patients have valuable insights when it comes to living with a disease including the treatment and management of that disease, which can be very useful to manufacturers when designing and conducting a clinical trial. Patient engagement may help mitigate some challenges associated with clinical trials including enrollment and retention, especially when protocols include lengthy follow up periods and/or frequent visits to the investigational site. By using a patient advisor, FDA believes these common challenges may be lessened.

The guidance covers many topics aimed at improving and encouraging patient engagement in clinical trials. It provides suggestions for engaging a patient advisor who can help with activities such as the informed consent documents, follow-up options, and providing input to help determine clinically meaningful endpoints.

FDA recommends involving a patient advisor in the early planning phases of the clinical investigation so that input can be incorporated into the protocol. The input from the patient advisor should be included in the final protocols and informed consent documents of an investigational device exemption (IDE) application so that FDA may review these as part of the IDE application. For ongoing studies, FDA recommends involving a patient advisor and the research coordinator to review and propose potential solutions.

With respect to how patient engagement with a patient advisor implicates a study’s institutional review board (IRB), FDA notes that these patient engagement activities involve interactions that are consultative or advisory in nature. Therefore, FDA wouldn’t generally consider these activities to constitute research and IRB requirements generally would not apply. In contrast, interactions between the patient and the investigator usually include collecting information as part of a research plan. These interactions are generally in the context of clinical investigations and therefore must satisfy the applicable FDA requirements.

FDA encourages patient engagement and recommends sponsors utilize the informational meeting through the Q-Submission Program in order to discuss patient engagement approaches.

FDA finalized its guidance on Annual Report for Approved PMAs on December 16, 2019. This final guidance document clarifies and expands upon the 2014 draft guidance on PMA annual reports. The final guidance recommends the addition of several columns in the annual report’s “changes table,” including type of change (design, labeling, manufacturing), description of the change, related changes, and why a change does not impact the safety and effectiveness of the device.

The guidance also provides some additional examples of rationales for device changes. Remember, annual reportable changes are limited to those that do NOT affect the device’s safety or effectiveness. Change summaries in PMA annual reports should be carefully drafted to ensure that the change is accurately captured and fully described, but you should avoid using language that implies that the change could have an effect on safety or effectiveness. Consider having your regulatory lawyer review annual report change summaries.

Change summaries that are disorganized or sloppily-written may raise a red flag with the FDA, resulting in questions, deficiencies, and awkward retrospective submissions and even present the prospect of an enforcement action.

If FDA believes that the changes reported in the annual report could affect the device’s safety or effectiveness, they will tell you submit the change in a PMA Supplement or 30-Day Notice—even though the change was already implemented. This is another reason why it is important to get the regulatory assessment right the first time—before the change is implemented.

On September 19, 2019, FDA issued a new draft guidance for its Safer Technologies Program for Medical Devices. The new voluntary program for certain medical devices and device-led combination products is expected to “significantly improve the safety of currently available treatments or diagnostics” and is intended for conditions that are less serious than those eligible for the Breakthrough Devices Program. Devices that are subject to review under PMA, De Novo classification request, or 510(k) submissions are eligible for the program.

The program supersedes the Expedited Access Pathway that was launched in 2015, and has been modeled on the principles of the Breakthrough Devices Program. The intent of this program is to “help patients have more timely access to these medical devices and device-led combination products by expediting their development, assessment, and review” while preserving FDA’s current statutory standards for “traditional” submission pathways (e.g., 510(k), PMA, De Novo).

There are two specific eligibility factors that must be met in order to be eligible for inclusion in the program:

    1. The device should not be eligible for the Breakthrough Devices Program due to the less serious nature of the disease or condition treated, diagnosed, or prevented by the device; and
    2. The device should reasonably be expected to significantly improve the benefit-risk profile of a treatment or diagnostic through substantial safety innovations that provide for one or more of the following:
      • Reduction in the occurrence of a known serious adverse event;
      • Reduction in the occurrence of a known device failure mode;
      • Reduction in the occurrence of a known use-related hazard or use error; or
      • Improvement in the safety of another device or intervention.

The draft guidance document goes into great detail regarding these factors as well as other considerations—including flexible clinical study design and prioritized and/or expedited review. At its core, this is another indication of FDA’s willingness to engage with industry and promote innovation.

If you have ever had to print and ship multiple voluminous premarket medical device submission to the FDA, you are likely thrilled about FDA’s recent Final Rule regarding electronic submissions and the corresponding guidance document, eCopy Program for Medical Device Submissions, that was issued on December 16, 2019. An “eCopy” is an electronic version of a medical device submission on a CD, DVD, or flash drive. Unlike other guidance documents, the FDA specifically states that this guidance does indeed contain “binding provisions” as it relates to standards, criteria for waivers, and exemptions per Section 745A(b) of the FD&C Act.

Under this new rule, only a single eCopy of the submission is required to be submitted to the FDA. Remember to include a signed hard copy cover letter with the electronic copy of the submission. FDA’s eCopy guidance document contains technical standards that should be carefully followed. If you fail to meet the eCopy technical standards, your submission will be placed on hold until a valid eCopy is received, resulting in a delay in your submission review. This transition to eCopy will likely save time and money for companies by eliminating the burden of printing, packing, and shipping paper copies of submissions to the FDA.

What are 10 things you can do to speed along your 510(k), PMA, or De Novo submission?

  1. Don’t guess. When in doubt, ask the FDA. Consider a pre-sub or 513(g) Request for Information. Proactive FDA interaction will save you time down the road.
  2. Know the FDA guidance(s) applicable to your device and submission pathway. Is there a Special Controls guidance?
  3. Engage an expert to compile and/or review your submission. Writing for the FDA requires a unique skill set.
  4. Do not promote your investigational device before it is approved—this is not allowed per 21 CFR 812.7. Reviewers often visit company websites to learn about a company and its device.
  5. Adequately budget and staff your assignment. An inadequately-provisioned ship may only make it half-way across the ocean.
  6. Establish reasonable timelines to clearance or approval.
  7. Don’t set out on the 510(k) pathway when your device belongs on the De Novo or PMA pathway. The path to clearance or approval is littered with companies that have chosen the wrong pathway and gone bankrupt as a result.
  8. Get it right the first time. Mistakes will shake the confidence of your FDA reviewer.
  9. Consider whether a pre-submission meeting is necessary, e.g., these are often unnecessary for less complex submissions.
  10. Work collaboratively with the FDA. Be firm when necessary. But remember that the Agency has a job to do. Don’t be combative or unnecessarily escalate disagreements. Use the CDRH Office of the Ombudsman if you have a concern about how your submission is being treated.

An age-old question: Are FDA guidances “binding”—i.e., do they have to be followed?

FDA guidance documents are not law or regulation. With limited exceptions, they contain “non-binding recommendations.” What does that mean?

To an outsider it means that they are optional recommendations. But those of us that have worked in this industry long enough know a company would be a fool if they failed to recognize FDA guidance for what it is: a true reflection of Agency expectations.

Companies are ill-advised to ignore them. You must stay abreast of FDA guidance documents in order to effectively do your job and meet business objectives, e.g., submit a 510(k) and obtain clearance. Why ignore the regulator? Doing so will only frustrate the FDA and impede your objective—a successful submission and a marketable device.

Failure to get your submission right the first time can delay product launch, prolong burn, and keep enhancements out of the hands of practitioners—which impacts patients.

Gardner Law has an intimate understanding of FDA’s regulations and current guidances related to regulatory submissions. We have summarized some of the recent guidance documents related to the FDA medical device submissions process above.

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Drafting regulatory submissions to the FDA requires specialized skills and an intimate knowledge of FDA expectations and requirements. Gardner Law has extensive FDA regulatory submissions experience, including face-to-face and remote interactions with the FDA to discuss and successfully negotiate resolutions to complex submission issues. Our experience and knowledge is based on a hands-on understanding of FDA regulations and guidance documents as well as extensive industry practice.

Amanda Johnston, J.D., is Regulatory Affairs Certified (RAC) by the Regulatory Affairs Professional Society (RAPS) and leads the Gardner Law FDA submissions team. We have worked on nearly every kind of FDA regulatory submission for drugs and medical devices: PMAs, IDEs, 510(k)s, De Novos, NDAs, 513(g) Requests for Designation, Small Business Certification Requests, Breakthrough Designation, annual reports, product change submissions/supplements, and pre-submissions (Q-Subs).

Whether you have a brand new product that you are looking to commercialize or need regulatory assistance with a currently-marketed product, we can help with all aspects of FDA regulatory submissions and strategy. Gardner Law also possesses deep knowledge about product advertising and promotion laws, health care fraud and abuse, compliance programs, sunshine transparency laws, quality management systems, clinical research requirements, FDA enforcement actions, and privacy law that enables us to provide full-service counsel to FDA-regulated companies.

Amanda Johnston, J.D., R.A.C.,
Sr. Attorney, Gardner Law

Amy Fowler, J.D., R.A.C.,
Counsel, Gardner Law

Mark Gardner, M.B.A., J.D.,
Managing Attorney, Gardner Law

Heather Potter, J.D.
Associate Attorney, Gardner Law

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