The U.S. Food and Drug Administration (FDA) recently released draft guidance on the new "Breakthrough Devices Program,"¹ which was established by the 21st Century Cures Act.² This new program supersedes and combines features of existing FDA programs, including the current Expedited Access Pathway (EAP) and the Priority Review Program, and is intended to expedite the development and review of breakthrough devices.

In general, breakthrough devices are new medical devices that provide:

• provide "more effective treatment or diagnosis of life-threatening or irreversibly debilitating human disease or conditions;" and
• represent "breakthrough technologies" for which no approved or cleared alternatives exist, that offer significant advantages over existing alternatives, or "the availability of which is in the best interest of patients."³

Sponsors can request entry into the Breakthrough Device Program by submitting a designation request. The draft guidance provides that sponsors should indicate which marketing application type (PMA, 510(k), or De Novo request) they intend to submit and include a rationale for the approach in support of their designation request.

It is important to remember that diagnostic tests are medical devices, and thus, some may qualify as breakthrough devices.

The FDA will issue a grant or denial decision for each breakthrough device designation request within 60 calendar days of receiving such a request. While the FDA's designation decision does not constitute a formal decision regarding the applicable regulatory pathway or device classification, the designation decision does indicate that the agency expects a submission of a PMA, 510(k), or De Novo request will be required based on the information provided and known at the time.

The draft guidance provides the following criteria for breakthrough device designation:

1. Device Provides for More Effective Treatment or Diagnosis. Important factors include: whether there is a reasonable expectation that a device could provide more effective treatment or diagnosis relative to the current standard of care, whether the likelihood of death is high unless the course of the disease is interrupted in a population or subpopulation, whether the disease or condition is associated with morbidity that has substantial impact on day-to-day functioning to be irreversibly debilitating for a population or subpopulation, among other factors.
2. Device Represents Breakthrough Technology. Important factors include: the potential for a device to lead to a clinical improvement in the diagnosis, treatment (including monitoring of treatment), cure, mitigation, or prevention of the life-threatening or irreversibly debilitating condition.
3. No Approved or Cleared Alternatives Exist. Important factors include: whether there is an alternative drug, biological product, or device that received FDA marketing authorization after premarket review for the same indications being considered and is consistent with the U.S. standard of care. In the absence of a well-established and documented standard of care, the FDA may consult with experts to determine whether an approved or cleared product is relevant to the current standard of care.
4. Device Offers Significant Advantages Over Existing Approved or Cleared Alternatives. Important factors include: the potential to reduce or eliminate the need for hospitalization, improve patient quality of life, facilitate patients' ability to manage their own care, or establish long-term clinical efficiencies, as compared to existing approved or cleared alternatives.
5. Device Availability Is in the Best Interests of Patients. Important factors include: whether the proposed device and indications for use provide another type of specific public health benefit; provide a benefit to patients who are unable to tolerate available therapy or whose disease is not responsive to available therapy; avoids serious harm associated with available therapy; address an unanticipated serious failure occurring in a critical component of an approved device for which there are no alternatives or for which alternative treatment would entail substantial risk of morbidity for the patient, among others.

Breakthrough device designation may be granted for multiple devices with the same proposed intended use. However, once a breakthrough device has been approved or cleared or has had a De Novo request granted, no other devices with the same intended use will be designated as a breakthrough device, unless the designation criteria above are satisfied in view of the first breakthrough device's market availability.

To expedite review and development of breakthrough devices, the new program implements seven principles, as follows:

1. Interactive and Timely Communication. Includes communication with the sponsor during device development and through the review process for Q-Submissions, Investigational Device Exemptions, PMAs, Premarket Notifications (510(k)s), and/or De Novo classification requests, and having assigned staff who are available to address questions by the institutional review committees within a reasonable time.
2. Pre/Postmarket Balance of Data Collection. Includes consideration of the amount of data that may be collected in the postmarket setting, rather than premarket, and the level of acceptable uncertainty in the benefit-risk profile at the time of approval.
3. Efficient and Flexible Clinical Study Design. Includes consideration of pre-specified endpoints regarding the minimum clinically meaningful effect, intermediate and surrogate endpoints or composite endpoints in some cases, and phrased study design.
4. Review Team Support. Includes regular training of review teams to ensure consistent and efficient application of the program principles.
5. Senior Management Engagement. Includes collaboration between the review teams and senior management to support efficient and timely dispute resolution.
6. Priority Review. All designated breakthrough devices will receive priority review status, which means the submission is placed at the top of the appropriate review queue and receives additional resources, as needed, but review times for breakthrough devices may still be longer due to novel scientific issues raised by the devices. Where multiple submissions are under review, the applications will be reviewed on a first-in-first-reviewed basis for each review cycle.
7. Manufacturing Considerations for PMA Submissions. On a case-by-case basis and at its discretion, the FDA may allow a sponsor to provide less manufacturing information in a PMA or inspect certain manufacturing sites after approval instead of prior to approval, depending on the date of the site's last inspection and the results of that inspection, among other factors. In cases where the FDA does not conduct a preapproval inspection, the agency intends to conduct an inspection within 12 months after approval.

Additionally, the FDA offers several options for sponsors of breakthrough devices to seek early interaction with the agency to expedite development of these devices. A sponsor may select one or more of the following options at any time before submitting a marketing application for the device.

1. "Sprint" Discussion. To support sponsors who need timely resolution of potentially novel issues on a specific topic within a set time period (e.g., 45 days). Parameters set forth for "sprint" discussions include: single topic with specific goals, defined interaction schedule, including planned participants, clear documentation of interactions and conclusions, and supporting materials that justify the proposed approach.
2. Data Development Plan (DDP). The FDA will work with sponsors to develop a DDP, or a high-level document that outlines data collection expectations for the entire product lifecycle and description of the balance of premarket and post-market data collection to help ensure predictable, efficient, transparent, and timely device assessment and review.
3. Clinical Protocol Agreement. The FDA will work with sponsors who choose to pursue a clinical protocol agreement. Upon agreement, the FDA will issue a letter documenting the agreement.
4. Regular Status Updates. The FDA and a sponsor may agree to have regular (e.g., bimonthly) status updates, which may be by email, teleconference, or in a face-to-face meeting.

The FDA's Breakthrough Devices Program offers manufacturers important agency resources, and expedited interactions and review, for devices that qualify for the program. It is important for device manufacturers that are developing novel devices for unmet patient needs to understand the qualifications for seeking admission into the program and to apply to part of the program in appropriate situations.