The FDA has been on a bit of a tear in publishing guidance for devices and generic drugs. Here we address the CDRH guidance issued between September 29th and October 25th 2017 and provide summaries of their content. Seven guidance listed below are final, and one is published for comment. Many are associated with requirements in the Medical Device User Fee legislation, MDUFA. Expect more of these moving forward into the MDUFA IV era.

Requests for Feedback on Medical Device Submissions: The Pre-Submission Program and Meetings with Food and Drug Administration Staff – Guidance for Industry and Food and Drug Administration Staff

The FDA issued this 57-page final guidance on September 29, 2017. It replaces a previous version of the guidance from February 2014 and incorporates changes identified in MDUFA IV. The changes include the scheduling of pre-submission meetings and FDA feedback on a variety of topics. Regarding the latter, the guidance lists a collection of guidance that addresses requests for FDA feedback.

Requests for FDA feedback include those associated with pre-submission programs (page 12), informational meetings (page 22), study risk determinations (page 23), formal early collaboration meetings (page 24), and submission issue meetings (page 25).

The guidance addresses how the FDA will respond to meeting requests, security screening to be expected at FDA facilities, and meeting conduct/activities after the meeting. And, finally, Appendix 1 begins on page 34 and provides recommendations for specific types of pre-submission meetings.

FDA and Industry Actions on De Novo Classification Requests: Effect on FDA Review Clock and Goals – Guidance for Industry and Food and Drug Administration Staff

This 7-page final guidance, issued October 2, 2017, describes the performance goals specified in the MDUFA IV Commitment Letter. It also addresses requests for device classification as either Class I or II received after October 1, 2017. The guidance identifies the actions that the FDA may take upon receipt of a device classification request, the performance goals for these requests under GDUFA IV, and the requester’s actions. It does not apply to a device “…that has already been classified…in an existing classification regulation.”

Briefly, the FDA may take three possible actions on a de novo classification request: they may grant the request, they may decline the request, or they may ask for additional information. If the FDA declines the request, the device remains in the class III category, and the guidance provides six situations where the request would be denied. Additional information can be requested by phone call, email, or letter. If the firm does not provide the requested information within 180 days after the request, the FDA may administratively withdraw the request.

De Novo requests for classification are subject to a user fee, and requests will not be processed in the absence of confirmed payment. The FDA will issue draft and final guidance to include a submission checklist that will ensure an efficient process for the classification process. Only one tier is given for this performance goal. The performance goals for the classification decision is 150 days. The FDA’s review goals for these decisions begin in 2018 at 50% and ending in 2022 at 70%.

Firms that request a classification decision prepare an initial request. They then can respond to the FDA’s request for additional information (which pauses the review clock) or ask that the request be withdrawn.

FDA and Industry Actions on Premarket Notification (510(k)) Submissions: Effect on FDA Review Clock and Goals – Guidance for Industry and Food and Drug Administration Staff

This 14-page final guidance issued October 2, 2017 replaces a guidance of the same title issued in October 2012. The guidance identifies the actions the FDA may take on 510(k)s under MDUFA IV, how these actions may affect goals from MDUFA III, the effect of 510(k)s submitted under MDUFA IV between 2018-2022, and industry actions that may be taken on 510(k)s.

The FDA may take a variety of actions on 510(k) submissions including:

  • Declaring the device to be substantially equivalent to a marketed predicate device
  • Declaring the device not substantially equivalent
  • Requesting additional information
  • Informing the firm that a 510(k) is not required because it is either not a device or is not a device subject to a pre-market submission
  • Issuing a notice of withdrawal of the 510(k) if requested information is not provided within 30 days of its request.  See 21 CFR807.87(l).  The FDA will now extend this to 180 days for which the firm will not need to request an extension.

MDUFA IV performance goals continue to commit to a 95% performance level to reach a substantially equivalent or not substantially equivalent decision in 90 days. This continues the goals in place from FY2015 though the average total time goal to the decision continues to decrease from 130 days in FY2015 to 124 days in FY2018 and 108 days in FY2022. For instances where the FDA does not reach a MDUFA decision within 100 days, 10 days over the targeted 90 days, they will issue a ‘missed MDUFA decision communication’ to the submitting firm. This communication will identify outstanding review topics, the reason for the FDA not making a final decision within the stated goals, and/or an estimated date of review completion.

FDA and Industry Actions on Premarket Approval Applications (PMAs): Effect on FDA Review Clock and Goals – Guidance for Industry and Food and Drug Administration Staff

This 15-page final guidance issued October 2, 2017 replaces a guidance of the same title issued in October 2012. This appears to be a companion document to the one immediately above, and between the two cover actions on device pre-market applications. This guidance addresses actions that may be taken for Premarket Approval Applications (PMA).

The FDA may take a variety of actions on an original PMA or PMA supplement including:

  • Issue an approval letter that marks the end of the FDA review.
  • Issue an approvable letter which identifies minor deficiencies that need to be addressed satisfactorily or states that satisfactory completion of an FDA GMP inspection is necessary before product approval. The FDA review clock is stopped in both cases until the actions are completed at which time they will issue an approval letter.
  • Issue a major deficiency letter stating that the application lacks significant information necessary to complete review. This can include a requirement for an alternative statistical method analysis, additional test data to ensure safety and efficacy, scientific rational for data in the submission, or new validation data and analysis.

The FDA review clock is stopped when this type of letter is issued and will resume when the response is received.

  • Issue a not-approvable letter for serious deficiencies. These will generally be preceded by a major deficiency letter to permit the applicant to address the concerns. The not-approvable letter will identify the deficiencies that need to be remediated for the application to be considered approvable. The FDA will stop the review clock and will restart the clock upon receipt of a response.
  • Issue a denial letter when the FDA has denied approval of the application. Again, the letter will identify all deficiencies that apply to the denial decision.
  • Also, the FDA considers a PMA to be voluntarily withdrawn if the applicant does not respond to an approvable letter, major deficiency letter, or not-approvable letter within 180 days. After 360 days, the FDA will notify the applicant that the PMA or associated supplement/amendment is voluntarily withdrawn. Upon resubmission of the PMA, it will be assigned a new PMA number and the applicant is subject to a new user fee payment.

The MDUFA III goals for FY2017 regarding ‘substantive interactions’ and ‘MDUFA decisions’ are duplicated in GDUFA IV for the years FY2018 – FY2022. The MDUFA IV ”Average Total Time to Decision” has marked reduction over those specified for MDUFA III. For MDUFA IV, the average total time to decision begins at 320 days in FY2018 and decreases to 290 days in FY2022 compared with 385 days in FY2017, the final year of MDUFA III.

Deciding When to Submit a 510(k) for a Change to an Existing Device.

This 77-page final guidance issued on October 25, 2017 represents finalization of a draft published on August 8, 2016. The guidance supersedes ‘Deciding When to Submit a 510(k) for a Change to an Existing Device’ from January 1997. The FDA states that the guidance is consistent with the least burdensome principles from section 513(i)(1)(D)(i) of the FD&C Act. The guidance references other device guidance (which are listed with links). It also provides detailed flowcharts and narrative descriptions for a variety of changes. The types of changes are broken into smaller sections identified as:

  • Main types of changes (Section V, Main Flowchart)
  • Labeling (Section V.A., Flowchart A)
  • Technology which includes engineering and performance changes (Section V.B., Flowchart B)
  • Materials changes (Section V.C, Flowchart C)
  • Technology changes for in vitro diagnostic devices that includes engineering, performance, and material changes (Section V.D., Flowchart D), and finally
  • Considerations for risk-based assessments of modified devices that includes examples, documentation, and significant terminology (Section V.E.)

Deciding When to Submit a 510(k) for a Software Change to an Existing Device

This 28-page final guidance was issued on October 25, 2017 and finalizes a draft of the same title issued in August 2016. The FDA states that “…the intent of this guidance is to enhance the predictability, consistency, and transparency of the ‘when to submit’ decision-making process by providing a least burdensome approach, and describing in greater detail the regulatory framework, policies, and practices underlying such a decision, specifically as it relates to software changes.” This guidance will assist the industry and the Agency in determining whether software and/or firmware changes to a medical device may require submission of a new 510(k) premarket notification. This guidance references and provides links to guidance documents on related topics. Similar to the preceding guidance in this article, the least burdensome provisions of the FD&C Act apply.

The guidance principles to be used in determining whether the changes in software or firmware warrant a new 510(k) submission include the following:

  • If the changes are made intending to significantly affect the safety or efficacy of a device, a new 510(k) submission will likely be required. Even changes that are not intended to affect the device safety or efficacy should be evaluated for its potential impact in this area.
  • The firm should conduct a risk-based assessment to identify and consider all new risks or changes in risks that have been previously identified. This information should inform the analysis of whether a new 510(k) submission.
  • The firm should consider the potential unintended or unplanned consequences on the device. The consequences can include potential effects on device drivers/software code and the possible need to update other components to ensure compatibility.
  • Risk management is mentioned though out the guidance. This section concludes by saying “…if the overall probability of occurrence of harm cannot be estimated, the estimation of risk should be based on the severity of harm alone.”
  • Verification and validation must be completed regardless of whether a new 510(k) may be required.
  • Multiple simultaneous changes should be evaluated both individually as well as in aggregate to determine their potential impact on the device.
  • The firm should determine whether the device incorporating the changes remains ‘substantially equivalent’ to the unmodified device.  This evaluation should be conducted each time a change is made.
  • Where required by the regulations, changes made to the device should be documented consistent with the requirements of the firm’s Quality System.
  • When a new 510(k) submission is needed appropriate, the submission should describe all changes made since the last cleared 510(k). This section addresses additional detail for the new 510(k).
  • Firms are reminded that even for those who follow this guidance, the FDA may not determine the revised/refined device described in the new 510(k) to be substantially equivalent to device addressed in the original 510(k).

New CDRH Learn Module – Medical Device User Fee Amendments of 2017 (MDUFA IV): An Introduction

The CDER Learn webpage contains eight modules that are intended to provide information that is “comprehensive, interactive, and easily accessible.” New sections have been added to the “Basics” module and include an ‘Introduction to MDUFA IV’ and a section on ‘FURLS Device Registration and Listing Module for Annual Registration.’ The first includes the Presentation, Printable Slides, and a Transcript. The section on FURLS includes only the Presentation.


Breakthrough Devices Program

The FDA published a 25-page draft guidance dated October 25, 2017. This guidance is written in support of the 21s Century Cures Act and GDUFA IV. When finalized it will replace guidance titled ‘Expedited Access for Premarket Approval and De Novo Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions’ published in April 2015.

The guidance includes four major sections and two appendices, including:

  • Program Principles including communication, pre and post-market data collection, clinical study design, review team support, senior management engagement, priority review, and manufacturing considerations for PMA submissions (pages 2 – 6)
  • Program Features including breakthrough device sprint discussion, data development plan, clinical protocol agreement, and status updates (pages 7 – 11)
  • Designation Request including designation criteria and considerations, designation review process, and designation withdrawal (pages 11 – 19)
  • Appendix 1 describes information that may be useful in assembling a Data Development Plan (pages 20 – 22)
  • Appendix 2 provides an example of a Breakthrough Device Designation Request (pages 23 – 25)