The US Food and Drug Administration (FDA) has released a long-awaited draft guidance document outlining an expedited approval pathway that can be used by sponsors of medical devices intended to treat life-threatening or "irreversibly debilitating" diseases or conditions.

Background: EAP Basics

The guidance, which for months has been rumored to be near completion, introduces the "Expedited Access Premarket Approval" program, or EAP for short. Regulatory officials said it is a continuation of FDA's earlier Innovation Pathway, a 2011 initiative meant to fast-track innovative medical devices.

FDA said it believes the program "will help patients have more timely access to these medical devices by expediting their development, assessment and review, while preserving the statutory standard of reasonable assurance of safety and effectiveness for premarket approval."

The program will involve sponsors and FDA working closely together, both to communicate and resolve issues as they arise and in the development of a "data development plan specific to the device" that will outline the clinical data that the sponsor intends to use in support of the device's approval and when that data will be collected (premarket or postmarket).

FDA called that data development plan a key aspect of the EAP, as it will "help assure predictable, efficient, transparent and timely device assessment and review." Especially crucial will be determining which data can be collected after the device is granted approval.

"Getting the right balance between premarket and postmarket data collection-specifically, where appropriate, a greater reliance on postmarket collection-can reduce the extent of premarket data submission and directly impact when patients will have access to high-quality, safe and effective medical devices," FDA wrote.

While the exact degree of certainty FDA requires to ensure that a healthcare product is safe and effective is difficult to quantify, and has been the bane of more than a few drugs and biological products seeking expedited approval, FDA said it would approve EAP devices if "uncertainty is sufficiently balanced by other factors," such as the device's likely benefit, controls on the device's use, and the benefit of early access to the device by patients.

What is the EAP?

FDA's guidance document, Expedited Access for Premarket Approval Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions, goes on to explain the requirements for participating in the EAP.

Sponsors will first need to request a designation from FDA that their device is an "EAP Device," known as "EAP Designation." If FDA grants that designation, the sponsor and FDA will then negotiate a Data Development Plan, which will lead to the submission and review of a premarket application (PMA) for the EAP Device.

If approved, FDA will then require robust postmarket data collection and evaluation.

Interestingly, FDA said it may, "at its discretion," permit device manufacturers to "provide less manufacturing information in their PMA application," or even skip premarket inspections of manufacturing sites. Those have traditionally been hurdles for manufacturers looking to bring their products to market very quickly, as sites are required to be inspected by FDA prior to a product coming to market. While FDA didn't say it would waive the requirements in all cases, some manufacturers-those with well-established manufacturing operations that have been inspected recently and without a Warning Letter or 483-might stand to benefit most of all. FDA said it will instead inspect the facilities soon after product approval.

Continuing approval of the devices will also depend on the sponsor meeting postmarket data collection commitments-an important requirement given the incomplete data FDA may be basing its approval decisions on.

Which Devices will Qualify?

Which devices qualify for "EAP Designation" as an "EAP Device?"

First, the device must be "intended to treat or diagnose a life-threatening or irreversibly debilitating disease or condition." While the definition of "life-threatening" is defined in the guidance and is relatively straightforward, the definition of "irreversible debilitating" contains some interesting leeway for sponsors.

For example, while FDA says that "short-lived and self-limiting" morbidities will not qualify a condition or disease for EAP status, "persistent or recurrent" conditions or diseases may qualify based on their debilitating (and perhaps cumulative) effects.

"Whether a disease or condition is "irreversibly debilitating" is based on its impact on such factors as survival, day-to-day functioning, and the likelihood that the disease or condition, if left untreated, will progress to a more serious disease or condition," FDA explained.

The second major qualification factor for EAP status is that the device needs to meet at least one of four criteria:

1. The device represents a breakthrough technology that provides a clinically meaningful advantage over existing technology.
2. No approved alternative treatment or means of diagnosis exists.
3. The device offers significant, clinically meaningful advantages over existing approved alternatives.
4. The availability of the device is in the best interest of patients (e.g., addresses an unmet medical need).

The fourth of these points includes several sub-considerations, such as whether the device can avoid major harms that exist with presently available therapies, whether the new device can improve adherence to therapies, or whether it can reduce adverse interactions which occur with other therapies.

FDA made clear that IVDs are eligible for this pathway, and may find their justification through this fourth criteria.

Third and finally, EAP status is contingent upon the submission of a data development plan, which must contain a description of data sufficient to determine if there is a reasonable assurance of safety and effectiveness. For example, a selected surrogate endpoint would need to be reasonably likely to predict clinical benefit in patients, FDA wrote.

The plan should also include a timeline for postmarket data collection.

What Makes an EAP Device Safe and Effective?

FDA said it intends to accept surrogate endpoints, intermediate endpoints, smaller clinical trials, quicker clinical trials, and companion diagnostics to help bring devices to market more quickly. The acceptable use of each of these metrics is discussed at length in the guidance.

FDA also said it will take into account 10 factors when evaluating the probable benefit-risk ratio of a device:

1. Premarket (clinical or non-clinical) data demonstrate that the probability of serious harm is low.
2. Postmarket patient exposure to the device prior to the required submission of postmarket data to FDA will be small.
3. The device is non-implantable.
4. The sponsor has a proven track record of a robust quality system.
5. A Data Safety Monitoring Board will be used in the postmarket study.
6. User training to help mitigate the probable risks of the device, which is described in the proposed labeling for the device.
7. The sponsor will provide patient labeling.
8. There is valid scientific evidence to demonstrate that the intended patient population is willing to tolerate the probable harm of the device in light of the level of uncertainty about the probable benefits and/or probable risks of the device
9. There is a high likelihood that postmarket surveillance can quickly identify instances of serious patient harm.
10. There is a high likelihood that the required postmarket data collection will be completed in a timely manner.
11. The proposed postmarket data study is well-designed and feasible, taking into account the likelihood that patients will participate in the study once the device has been approved.

Based on the data limitations, FDA said it may improve "certain labeling requirements" on the devices to explain to consumers the limitations of the data on which its approval was based. FDA recently approved a similar guidance document for drugs approved under expedited approval pathways.

EAP Impact

In a statement, FDA regulators were quick to say that the EAP is "not a new pathway to market," but is instead meant to be a "collaborative approach to facilitate product development" using existing regulatory authority granted to it by Congress. "While other existing device programs have focused on reducing the time for the premarket review, EAP also seeks to reduce the time associated with product development," FDA explained.

However, EAP designation will afford companies an interactive review with FDA to support a "least burdensome" approach to development and regulatory review, priority review status, and potentially the involvement of senior FDA management officials and a cross-disciplinary case manager.

What remains to be seen is industry's interest in the programs, and whether FDA can support that interest. In the pharmaceutical sector, FDA's expanded use of expedited access programs has led to a slow decline in approval times as more and more products seek market access through the programs. Because the reviews require more FDA resources than traditional reviews, that means slower approvals for other applications seeking expedited approval. FDA may ultimately need additional resources to support the EAP program if it attracts similar amounts of interest from device manufacturers.

What also remains to be seen: Whether devices sponsors will meet their end of the bargain in collecting data in postmarket settings. It sometimes becomes difficult to enroll patients in trials once a product has been approved, meaning some sponsors-even those that try to collect data-may be unable to meet FDA's requirements, or meet them in the agreed-upon time. Whether FDA will be flexible or will readily revoke approval for devices which fail to obtain the agreed-upon data will be a major point to watch going forward.

FDA will be accepting comments on the guidance for 90 days.

Expedited Access for Premarket Approval Medical Devices Intended for Unmet Medical Need for Life Threatening or Irreversibly Debilitating Diseases or Conditions (FR)

FDA Press Statement on the EAP Program