By Allyson B. Mullen –
The 21st Century Cures Act (Cures), signed into law in December 2016, established a program to provide priority review and management attention for breakthrough devices. We discussed the new section of the law in our earlier post on Cures (here). The law required FDA to issue a draft guidance regarding this program by November 7, 2017. On October 25, 2017, CDRH issued the required draft guidance, nearly two weeks ahead of the statutory deadline.
The guidance outlines the elements of the breakthrough device program, the key components of which were set out in Cures. Cures set out the definition of a breakthrough device, and the guidance provided additional clarification regarding how it will interpret these definitions. For example, one prong of the definition is that a proposed device “provides for more effective treatment.” The guidance explains that the Agency cannot know for certain at the early stage of development when breakthrough status is requested if a device will in fact provide more effective treatment. Therefore, the Agency will consider “whether there is a reasonable expectation that a device could provide for more effective treating or diagnosis relative to the current standard of care.” Similarly, when assessing whether a device offers “significant advantages over existing approved or cleared alternatives,” the Agency will consider the “potential” as compared to commercially available alternatives.
Another element of the definition is that a device be a “breakthrough technology.” When considering this prong, the Agency will evaluate “the potential for a device to lead to a clinical improvement in the diagnosis, treatment (including monitoring of treatment), cure, mitigation, or prevention of life-threatening or irreversibly debilitating condition.” Combination products that include a device constituent part will also be eligible for breakthrough device designation.
To request breakthrough status, a sponsor should submit a pre-submission. The draft guidance provides an example of such a request. A request should explain how a proposed device meets the definition of a breakthrough device as set out in Cures. The draft guidance indicates that the Agency will review and respond to such a request within 60 calendar days. It is worth noting that this timeline is twice as long as the current EAP program. The Agency intends to interact with the sponsor by day 30 and may request additional information, if needed in order to make a decision regarding breakthrough status.
The guidance indicates that manufacturers participating in the program will have the option of several ways in which to interact with the Agency during the review process. These options include:
Sprint Discussions. This type of interaction is essentially a high-speed pre-submission with the goal of resolving a disagreement in a pre-specified time period (a timeline is proposed by the sponsor in the meeting request). A sponsor requests a sprint discussion through the pre-sub process. It is intended to be a “highly interactive” process. The guidance provides an example of a sprint discussion including a timeline.
Data Development Plan (DDP). A sponsor can request that the Agency review and come to an agreement on a DDP prior to execution. A DDP can cover all clinical and non-clinical testing planned for a proposed breakthrough device. Review of a DDP is requested through a pre-submission. The DDP is an optional element of the breakthrough device program whereas it was a key aspect of the Expedited Access Program (EAP), its predecessor.
Clinical Protocol Agreement. A sponsor can request that the Agency review and agree to a planned clinical protocol for a breakthrough device prior to execution. The Agency agreement will be binding, with a few exceptions enumerated in the guidance. A clinical protocol agreement is requested through the pre-submission process.
Regular Status Updates. A sponsor can request regular periodic updates with the Agency (presumably the reviewing Division, including management, but the guidance does not say specifically). Regular status updates will be scheduled by FDA and the sponsor; a pre-submission is not required.
The guidance also expands on a number of elements of the program. For example, the guidance specifies that CDRH staff working on breakthrough devices will undergo specific training and “will be experienced with innovative approaches to regulatory science and clearly communicating FDA’s expectations during the device development process.” There are no specifics as to what specific criteria breakthrough device reviewers will need, but it is a good sign that the guidance commits to using experienced reviewers for these novel, clinically meaningful devices.
The guidance also states that breakthrough devices will receive priority review. The guidance also acknowledges that breakthrough devices often take longer to review because of the novel elements contained in these devices. In order to expedite the review process for breakthrough devices, CDRH requests that sponsors equally commit to resolving scientific and regulatory issues expeditiously during the review process.
For PMA devices, the guidance indicates that based on FDA’s discretion, the Agency will allow sponsors to provide less manufacturing information for breakthrough devices. Specifically, the guidance says that it may forego a preapproval inspection in certain circumstances. The guidance indicates,
Manufacturers with no inspectional history will require a preapproval inspection; and
FDA may postpone a preapproval inspection to after approval for:
manufacturers inspected within two years prior to the PMA filing date if the inspection results were No Action Indicated (NAI) or Voluntary Action Indicated (VAI) and FDA deems the inspectional results relevant to the pending PMA; and
manufacturers inspected between two and five years prior to the PMA filing date if the inspection results were No Action Indicated (NAI) or Voluntary Action Indicated (VAI) and FDA deems the inspectional results relevant to the pending PMA so long as the manufacturer provides:
a declaration stating that all activities at the relevant manufacturing site comply with the QSR; and
risk management documentation (e.g., in compliance with ISO 14971) indicating that risks associated with the device under review have been reduced to acceptable levels.
Once finalized, this guidance will replace the current Expedited Access Pathway (EAP) program. The EAP program was only established two years ago, in 2015. The breakthrough device program is very similar to and contains significant features of the EAP program. However, the draft breakthrough guidance does not address what will happen to devices that have been granted EAP status under the existing program. Industry relied on the existing EAP program to gain appropriate priority status for novel devices. It would be unreasonable for CDRH to require that manufacturers with EAP status for devices under development to obtain a new breakthrough device status. We hope that CDRH will address this gap before the breakthrough guidance is finalized.