FDA’s final guidance describing how the risks and benefits of devices are considered during pre-market reviews excludes 510(k)s from its scope after industry objected to inclusion of 510(k)s in draft guidance issued last summer.

Released March 27, the final guidance also includes information on risk-benefit determinations for de novo classification petitions that was not included in the August 2011 draft version. (See Also see "Risk-Benefit Guidance Aims To Improve Pre-Market Review Predictability" - Medtech Insight, 22 August, 2011..)

Device center reviewers “will begin applying the guidance to incoming PMA and de novo submissions and to submissions already under review with decisions beginning on May 1,” the agency said.

The eagerly awaited guidance outlines the systematic approach FDA device reviewers will take when making risk-benefit determinations and explains the various principal factors to be considered by the agency during device and diagnostic reviews. In particular, the guidance describes an approach that takes into account patients’ tolerance for risks and perspectives on benefits, as well as the novelty of the device.

The first-of-its-kind guidance document “clarifies this process for industry, which will provide manufacturers with greater predictability, consistency and transparency in FDA decision-making while allowing manufacturers and the FDA to use a common framework for benefit-risk determinations,” CDRH Director Jeffrey Shuren said in a statement.

AdvaMed raised concerns with the earlier draft that application of a general risk-benefit paradigm to 510(k) devices, as suggested by the draft guidance, “would not be consistent with statute and would potentially not allow for the marketing of devices with the best possible benefit-risk profile.”

Similarly, device maker Cook Group commented last November that “the statutory requirements for 510(k) clearance do not include risk-benefit determination. ... We respectfully request that 510(k)s not be included in the scope of this guidance document.”

The draft had specified 510(k) applicability “in limited cases.” FDA addressed 510(k) issues, including when clinical data might be needed for such submissions, in separate draft guidance last December. (See Also see "Changing The Paradigm: 510(k) Draft Guidance May Raise New Questions" - Medtech Insight, 9 January, 2012..)

FDA notes that it added de novo classification petitions to the scope of the final guidance after November comments from Novartis requesting further clarification of the draft document’s principles in the context of de novo petitions. The de novo program, created in 1997, is meant for low- to moderate-risk devices that cannot be found substantially equivalent to anything already on the market. The agency reviews de novo petitions to determine whether general and/or special controls provide reasonable assurance of safety and effectiveness necessary to support a classification.

“Since FDA’s review of the de novo and PMA submissions require a similar benefit-risk determination, FDA determined that analysis criteria associated with the safety and effectiveness decision should be the same for all submissions reviewed in the context of reasonable assurance of safety and effectiveness,” FDA explained in an email to “The Gray Sheet.”

“For these de novo submissions, the risk should fall within the low- to moderate-risk category for the device, so the benefit would not necessarily need to be as great as it would for a PMA,” the agency noted.

The guidance aims to provide “greater predictability, consistency and transparency in FDA decision-making while allowing manufacturers and the FDA to use a common framework for benefit-risk determinations” – CDRH Director Jeffrey Shuren

Guidance Applies During R&D Too

The final risk-benefit guidance also clarifies that the concepts discussed in the document are applicable to the medical device development process “from design to market.”

AdvaMed and others had raised concern that the draft version did not make it clear whether the risk-benefit determination comes at the end of a review or is part of the ongoing review and discussion with the device’s sponsor.

“Our overarching concern [with the draft guidance] is that it appears that benefit-risk considerations are not addressed until the end of a clinical investigation,” AdvaMed said in November comments on the draft. Risk-benefit factors “should be considered at the beginning and throughout the product development process, especially during clinical trial design,” the group said.

The final guidance states that risk-benefit factors “should be considered during the design, non-clinical testing, pre-investigational device exemption (IDE), and IDE phases as well as in assembling and assessing PMA applications or de novo petitions.”

In an effort not specifically addressed in the guidance, CDRH is adopting new statistical “decision analysis” tools to support risk-benefit decisions with more objective, quantitative factors. The center plans to apply the tools in the near term to the process of approving IDEs for early-stage trials as part of its nascent “Innovation Pathway.” (See Also see "Risk And Benefit, Quantified: CDRH Expands Use Of New Statistical Framework" - Medtech Insight, 2 January, 2012..)

The guidance includes a worksheet for device reviewers that incorporates the principal factors influencing risk-benefit determinations, such as the type, magnitude and duration of a risk or benefit, the probability that a patient will experience the risk, patient tolerance for risk, availability of alternative treatments, and the value the patient places on treatment.

Worksheet analysis will be described in a PMA’s summary of safety and effectiveness data, and in the decision summary review memos for de novo decisions, FDA notes. This will “increase the transparency of the decision-making process,” FDA said.

Among the changes made in the final guidance from the draft version was the addition of worksheet templates filled out with hypothetical examples of how reviewers might use the worksheets.

The final guidance also adds an appendix explaining the intersection of the guidance with ISO 14971 – an FDA-recognized standard that provides device makers with a framework to manage device risks.

The device center notes that it will train its reviewers on the guidance to assure its consistent application, as well as develop training for industry to help device sponsors “understand how CDRH will apply the guidance.”

Separately, CDRH is in the midst of initiating its first ever survey designed to measure how much risk patients would likely be willing to tolerate in order to achieve a potential benefit from a device, with the focus on obesity devices. (See Also see "Obesity Devices: Planned Risk-Tolerance Survey Could Impact CDRH Decision-Making" - Medtech Insight, 16 January, 2012..)

FDA’s Final Risk-Benefit Guidance Excludes 510(k)s, Adds De Novo Petitions

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