The U.S. Food & Drug Administration’s (FDA’s) Least Burdensome Provisions: Concept and Principles: Guidance for Industry and Food and Drug Administration Staff, February 5, 2019, states that “medical device regulation should be least burdensome across the total product life cycle.” This means that manufacturers are expected to provide “the minimum amount of information necessary to adequately address a relevant regulatory question or issue through the most efficient manner at the right time.” The FDA observed that this approach should “ensure that patients have access to high-quality, safe and effective medical devices.”
Congress added the “least burdensome” provisions to the Federal Food, Drug, and Cosmetic Act (FFDCA) under the Food and Drug Administration Modernization Act of 1997 (FDAMA). Congress enacted additional least burdensome provisions to the FFDCA through the FDA Safety and Innovation Act (FDASIA) and the 21st Century Cures Act (Cures Act) of 2016. FDASIA and the Cures Act provided statutory updates that clarified the original least burdensome provisions and further recognized the role of post-market activities in relation to premarket decisions.
The 2019 Least Burdensome Guidance replaces the Least Burdensome Provisions of the FDA Modernization Act of 1997: Concept and Principles; Final Guidance for FDA and Industry (“2002 Least Burdensome Guidance”). The draft and final versions of this guidance document have broadened the scope of impacted device submissions as compared with the 2002 Least Burdensome Guidance. See additional information at drinkerbiddle.com. The scope of the 2019 Least Burdensome Guidance is discussed further below.
This guidance document and the 2002 Least Burdensome Guidance define the term “least burdensome” differently. The 2002 Least Burdensome Guidance defines it as “a successful means of addressing a premarket issue that involves the most appropriate investment of time, effort, and resources on the part of industry and FDA.” The 2019 Least Burdensome Guidance defines “least burdensome” as “the minimum amount of information necessary to adequately address a relevant regulatory question or issue through the most efficient manner at the right time.”
“The least burdensome concept and this guidance apply to all products that meet the statutory definition of a device, including device constituent parts of combination products. The policy in this guidance applies to all activities (premarket and post-market actions) pertaining to the regulation of medical devices.”
The 2019 Least Burdensome Guidance document states that the FDA and industry should apply the following guiding principles when taking a least burdensome approach:
The 2019 Least Burdensome Guidance document provides examples, grouped by the least burdensome definition’s three elements: (1) the minimum information necessary, (2) the most efficient means and (3) the right time.
The “minimum information necessary” element supports the idea of leveraging existing data and real-world evidence (RWE) when practicable. The FDA’s “six-year rule” provides an example of leveraging existing data. Under the six-year rule “[the] FDA may use safety and effectiveness data from clinical or preclinical tests or studies, six years after PMA approval, in order to approve another applicant’s device, establish a performance standard or special control, or classify or reclassify another device under section 513 of the [FFDCA].”
As an example, the FDA used the six-year rule in its own initiative to support reclassification of stair-climbing wheelchairs and sharps needle destruction devices from Class III to Class II with special controls. The FDA and industry also leveraged RWE generated from a registry to support expanded indications for use of a cryosurgical tool.
Use of nonclinical data in lieu of clinical data, when appropriate, also is in keeping with the least burdensome principles’ “minimum information necessary” element. This guidance document states that the “use of descriptive information, in vitro studies, computer modeling and simulations, and/or animal performance data … could [also] be responsive to an outstanding regulatory question” and “should be considered before requesting clinical data.”
Additionally, this guidance instructs the FDA to implement a “bottom up approach to data requests.” This means the FDA should first consider whether descriptive information is sufficient in response to one of its requests. If descriptive information is insufficient, then the FDA should consider whether nonclinical performance testing or analytical studies using clinical samples address the issue adequately. If analytical or nonclinical bench testing, nonclinical animal testing, or biocompatibility studies are insufficient, then this guidance states the “FDA may request clinical performance data.”
The “most efficient means” element of the least burdensome principles means that the FDA and industry should try to maximize efficiency when obtaining or providing the evidence necessary to meet regulatory standards. This element involves weighing the benefits and risks, among other things, as part of the regulatory decision-making process for medical devices.
When determining a device’s safety and efficacy, the FDA considers, among other factors, the extent (e.g., probability, severity/magnitude, and duration) of benefits and risks. This means that a positive decision may be rendered with respect to a device even if it has probable risks. “For example, despite the occurrence of serious adverse events and death in clinical studies and OUS registries for a mitral valve repair device, FDA determined that there was a narrow patient population with low life expectancy and quality of life for which the probable benefits outweigh the probable risks.” There, the FDA found the device “provided an unmet clinical need” for certain patients who were not candidates for surgery. Taking into account the benefit-risk analysis, the FDA determined the device had a reasonable assurance of safety and effectiveness for this narrow patient population.
The “most efficient means” element also advances the idea that administrative burdens should be reduced. This guidance document lists bundling marketing submissions to reduce redundancies and having industry submit materials electronically as two forms of “streamlining” in keeping with the least burdensome principles. This guidance also suggests that the FDA should use global harmonization through alignment with international regulatory authorities as a way to increase efficiency.
The “right time” element of the least burdensome concept emphasizes the importance of striking “the right balance between premarket and post-market information needs …” This means that the FDA should request only the information that is necessary to make a specific regulatory decision. This guidance document promotes the idea that in certain cases safety and effectiveness questions may be answered appropriately in a post-market setting. In some cases, the FDA has determined premarket review is not required to assess a device’s safety and efficacy.
The “least burdensome” principles of the 2019 Least Burdensome Guidance direct manufacturers to provide “the minimum amount of information necessary to adequately address a relevant regulatory question or issue through the most effective manner at the right time.” This guidance now broadens the scope of impacted device submissions as well as pre- and post-market activities, and the least burdensome concept applies “to all products that meet the statutory definition of a device, including device constituent parts of combination products.”