A New CDER DMF Pathway for Device Constituent Parts with Electronics or Software

The FDA recently released a draft guidance for a new type of Drug Master File (DMF) that presents a new regulatory pathway option for drug-device combination products submitted to CDER. The October 29, 2019 guidance outlines the special case for a “platform” device constituent part with electronics and/or software (e.g., controls or tracking apps) that could be used for multiple drugs for the same company or multiple companies. (Type V DMFs for CDER-Led Combination Products Using Device Constituent Parts With Electronics or Software; Guidance for Industry https://www.fda.gov/media/132043/download )

Overall, the guidance is a positive development in that this type of detailed device information may be difficult to place in drug submissions and this approach may help facilitate consulting reviews by experts at CDRH. In my review of the draft, I found that it provided clear guidance for the expected content of this Type V DMF, while allowing many content options and alternatives to a DMF depending on the technology and the likely relevant or required disclosures. Notably, it also recognizes alternative regulatory pathways that could be an option for this content (e.g., CDRH Master File for Devices (MAF), 510(k)s, PMAs, De Novo applications, etc.). Otherwise, it reiterates the long-standing guidance for Type V DMFs (FDA-Accepted Reference Information) including the need to submit a request to FDA that would allow filing of this type of DMF submission. ( https://www.fda.gov/drugs/guidances-drugs/drug-master-files-guidelines )

Summary of the Guidance

The guidance is specific to device constituent parts with electronics and/or software that meet the statutory definition of a device and perform functions, including those that:

  • “Facilitate drug delivery in a manner that may include patient input or analysis (e.g., an electromechanically driven pen injector with software that allows input of patient or dosing information or that analyzes dosing or device use information)”

  • “Provide information that is used in making a decision regarding treatment, therapy, or drug delivery”

  • “Interface with other devices or systems to provide patient use or other information to the user or health care provider (e.g., physiological parameters)”

  • “Control or drive the features of the user interface.”

So, clearly, this guidance is targeted at current and future technologies associated with drug delivery and may address many adherence tracking features and potentially mobile apps. It closes an important guidance gap for the types of submissions available for these new combination product technologies as they evolve. Also, as a regulatory matter, Type V DMFs, as FDA noted, allow certain flexibility outside of requirements in section 745A of the FD&C Act, particularly regarding eCTD formatting. However, electronic submissions are still the only means of submission of these DMFs, which may be a new challenge for device partners to pharma companies or suppliers of the technologies involved.

The guidance walks the reader through the administrative procedures for the DMF including a “Letter of Intent”, the submission itself, and the administrative and technical review processes. For the submission content, the guidance outlines the technical information that could be provided under general subject areas:

  • Indication for use.

  • Device description.

  • Software information and documentation.

  • Human factors information and testing for the device.

  • Sterility assurance.

  • Shelf life/Expiration date and testing.

  • Biocompatibility information and testing.

  • Electrical safety and electromagnetic compatibility testing.

  • Bench testing.

  • Manufacturing information.

The guidance later explains the content and process for DMF amendments submitted for design or software changes to the device constituent part including testing the device or the combination product. Finally, it provides detailed expectations for DMF Annual Report submissions.

Analysis and opinion

This guidance will be most helpful to drug delivery device suppliers to pharma companies that may not be as familiar with CDER submissions but may be asked by their pharma partners to submit these DMFs as part of an overall combination product submission strategy. Pharma partners and suppliers will need to consider this DMF option as well as an NDA/BLA content option, a MAF submitted to CDRH, or a traditional 510[k), and consider FDA’s suggested list of expected content (above) to see what strategy makes sense. These decisions may not be easy, and the strategy chosen may need to be product specific. In any case, pharma companies would be shifting some of the regulatory submission/content burden and content strategy questions in these DMFs to their suppliers.

DMFs, MAFs and 510(k)s are now often referenced in INDs, NDAs, and BLAs for delivery devices or device constituent parts (without electronics or software) so these strategy questions are not entirely new. (The new draft guidance may also be appropriate for non-electronic/software device constituents assuming that Type III DMFs are not mandated for these devices.) Below are some of the key differences in these reference approaches.

DMF to CDER

  • Highly formal and administrative but with relevant content expectations

  • Electronic submission to FDA gateway per guidances

  • Annual reports required

  • Must be kept current for all changes to the device constituent part [21 CFR 314.420(c)] and must notify “referencers” of them

  • FDA has the option to review submitted changes/modifications at any time

  • Suppliers can keep technical information confidential

  • FDA makes information requests (IRs) to DMF holders during IND/BLA/NDA reviews – applicant learns of the IRs but are not informed of their nature or risk to the submission

MAF to CDRH

  • Flexible format and submissions (paper plus required “eCopy”)

  • Anything “substantive” may be submitted

  • Retains confidentiality (with statements limiting FOIA requests)

  • Pharma companies must rely on Supplier/Quality Agreements to ensure notification of all changes

  • Can submit MAF amendments only when a CDER supplement would be required – no annual reports required

  • With many amendments to the MAF, it can be difficult for CDRH reviewers to understand what is current for the device (no “replace” option for content)

510(k) to CDRH

  • Appropriate only for re-usable devices or those that can be user-assembled (e. g., certain needle safety devices)

  • Design change reporting follows CDRH guidances [e.g., special 510(k)s; non-filing justifications]

  • Can be difficult to address indication changes and specific differences relevant to individual NDAs/BLAs

  • Can be difficult to overcome FDA preference for single marketing applications (i.e., to CDER)

IND/BLA/NDA to CDER

  • No referencing required – device details are included in the submissions

  • Tends to increase the size of the submission

  • Supplements to the submission are made only when that content needs to be changed for the submission to be current and accurate

  • A device TOC (“roadmap”) can establish content relevant to just the device or to the combination product [to facilitate appropriate reviews by CDER and CDRH

Some quick caveats about these options

  • While MAFs have been used to support BLA/NDA applications, per a 2017 FDA description of a MAF: “Master files in support of other products regulated by FDA, even though they may contain information previously submitted in an MAF, are to be submitted to the appropriate FDA center(s).” https://www.fda.gov/medical-devices/premarket-approval-pma/master-files Still, the new CDER draft guidance appears to allow MAFs.

  • A prevailing practice is to use GMPs/Design Changes approaches to document modifications as Change Controls when there is no impact on the BLA/NDA content and no need to file a supplement.However, modifications that alter technological characteristics that impact safety or performance may still raise the need for a supplement per 21 CFR 314.70. Note that there is nothing in this code that addresses device performance, software, or electronics so regulatory compliance risks are a challenge to assess. FDA is moving toward new guidances on established conditions and post approval changes to device constituent parts regulated by CDER which should provide additional clarity.

There are many requirements typically imposed by CDRH on software and electronics (EMI) and it may make some sense for suppliers of platform delivery devices that have electronic or software features to file the DMF according to this Center’s guidance. The potential (extensive) software documentation that may be expected under FDA guidances (Policy for Device Software Functions and Mobile Medical Applications, Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices, General Principles of Software Validation, Off-The-Shelf Software Use in Medical Devices) is going to be a struggle to understand for the level of software detail required in the DMF, but then software documentation doesn’t really belong in a BLA/NDA document in my view.  It’s also not clear if these CDRH-specific guidances will apply directly to a “CDER-led” review. I am not suggesting CDRH guidances should apply as they are not specifically mentioned in the DMF guidance and guidance conformance documentation for software could be quite burdensome for many low risk features that do not control drug delivery.

Likewise, electromagnetic compatibility test reports can be lengthy and might be better placed in a master file (DMF or MAF). The new draft guidance list of potential content also includes biocompatibility testing of device constituent component materials and suppliers bench testing, which could also be appropriate DMF content compared to an NDA/BLA section. On the other hand, functional stability testing, which may include accelerated parts aging and performance testing with representative drugs, might be better placed in the IND (for clinical trial supplies expiry dating) or the NDA/BLA, because the specific drug combined with the device often needs to be assessed together.

In my view, human factors test results and use error risk analysis are always better located in the drug submission because it is the pharma company that needs to address these topics for the drug, device, therapeutic indication, and expected users and their use environment. Further, there may be some confusion on this content placement based on FDA correspondence to drug companies from Type B/C meetings. In this correspondence, FDA says that human factors study reports are expected in eCTD Module 5 (clinical information), although these should be linked and discussed comprehensively in Module 3 (quality information) as a Design Validation activity. Human factors information in a DMF would likely be reviewed by CDER’s Division of Medication Errors and Prevention Analysis in any case.

The draft leaves many options open for both device developers as well as the pharma companies who reference those DMFs, both for approval/licensure or supplements. One of the issues pharma companies would face is not knowing specifically what content is in the DMF and the justifications, explanations and robustness of the test information that have been provided in the DMF that they are relying on. The regulatory risk to the drug product submission because of potential DMF content deficiencies should not be underestimated in my view.

DMF, MAFs and 510(k)s have frequently been referenced in drug submissions for non-electronic/software types of device constituent parts and it has been a workable regulatory strategy. However, in my experience, depending on the willingness of the supplier to provide their technical information, device content that could be placed in a master file can also be incorporated into the IND/BLA/NDA. This gives the pharma company complete control of the explanations and justifications specific to the total combination product, and often limits the submission to only device details critical to drug approval (e.g., descriptions of subassembly information and their assembly with the drug constituent part rather than details about every component). Also, while there may be an intent to supply and use a “platform” device constituent part, pharma companies will often request specific attributes or marketing-based appearance changes to these platforms that would be best described in the drug submission. In contrast, platform variants described in a supplier’s DMFs could become complex to explain and to reference individually or specifically for different companies’ drug submissions – the draft guidance points out that this specificity is expected. With this drug submission approach, it’s not a bad idea to have the supplier review limited BLA/NDA content for accuracy, especially if it involves any of their test data. Of course, for the drug submission strategy, Quality Agreements should always include a clause that suppliers inform their customers of all changes so that the pharma company can assess the need for BLA/NDA supplements in a formal Change Control process.

Regarding DMF amendments and drug supplements, there is one regulatory risk of note that is called out in the draft guidance. The guidance states: “A Type V DMF amendment may be submitted for changes to the device constituent part (e.g., design or software changes), testing of the device constituent part, or testing of the combination product for attributes related to the device constituent part.”  Regarding supplements, it then reminds NDA/BLA holders that:

“If an amendment to a Type V DMF is submitted and no supplement or annual report to an approved application is received, FDA intends to evaluate the changes reported in the DMF amendment to determine whether a supplement to one or more approved applications is needed. If an applicant has determined that a supplement is not necessary and FDA does not agree with that decision (refer to 21 CFR 314.70 and 314.97), FDA will notify the affected applicant. Applicants are responsible for determining whether submissions to approved or pending applications are necessary.”

It’s not clear exactly how this will work.  Will consulting reviewers at CDRH review these changes each time the DMF is amended (software changes could be numerous) or will these reviews fall to CDER CMC reviewers? Is a new CDER Manual of Policies and Procedures (MAPP) warranted to explain this to FDA staff? Will DMF policies for amendments follow a “when to submit a new 510(k)” approach or instead, a PMA supplement expectation? The 21 CFR 314.70 regulations are devoid of any specifics on these kinds of device changes, and industry can only hope that FDA will apply “least burdensome” principles in these reviews, relying also on the Design Control framework in 21 CFR Part 4 and GMP inspections to ensure continuing product safety and effectiveness. Nevertheless, non-filing justifications for minor software/electronic changes should be robust and well documented in change control documentation. It would be quite problematic to receive a letter from FDA requiring that a change that was reported in a DMF months ago should have been filed as an NDA/BLA supplement (maybe based on an insufficient DMF content or risk-related explanations). This news would be even worse if that change had already been implemented and the product released for distribution. 

The success of this DMF strategy will depend on FDA exercising discretion and following a risk-based approach in its regulation of combination products. But more so, it will require pharma companies and their suppliers to work together to develop a quality and patient-centric product, supply the right DMF and NDA/BLA content, and judiciously satisfy FDA Information Requests.  Otherwise, there will be both a significantly increased regulatory burden and a higher risk to regulatory approvals.

This review is entirely the opinion of the author who recognizes that others may have additional concerns or recommendations that the author has not addressed, or may have opposing or different opinions regarding this analysis.  Of course, all regulatory advice is only that; FDA is the final arbiter of the requirements for the submissions that it reviews. ©

Douglass Mead1 Comment