FDA is taking another stab at giving device companies advice on how to tell if a change they make to a 510(k)-cleared product warrants a new pre-market submission.

The agency issued a draft guidance document on the topic July 26. When finalized, it will replace a 1997 guideline that has caused some confusion among firms.

Under FDA regulations, changes to a 510(k)-cleared device's design, components, labeling or methods of manufacturer that could significantly affect its safety or effectiveness, or constitute a major modification to the device’s intended use, warrant a new 510(k). When those thresholds are not met, a company can simply document its decision not to file with FDA and launch the revision.

The latter instance is relatively common, and allows firms to make, for example, an array of aesthetic modifications or minor wording clarifications in labeling without having to undergo agency review. But there are also many gray areas regarding where the line should be drawn for “significant” or “major” changes.

The matter gained prominence in 2008 when Edwards Lifesciences temporarily withdrew a mitral valve repair device from the market following a patient complaint and subsequent inquiries from FDA and Congress into why the device was being sold without pre-market clearance.

Edwards had launched the device in 2006 based on its determination, relying on the 1997 guidance, that the difference between the new device and a prior valve repair device was not significant enough to warrant a submission. But FDA ultimately determined that a 510(k) was necessary and granted clearance for the modified product in 2009. (See “ Also see "Edwards’ Mitral Valve Repair Device Withdrawn, Under Scrutiny" - Medtech Insight, 8 December, 2008. ” – “The Gray Sheet” Dec. 8, 2008.)

Switch From Flowcharts To Case Examples

Both the 1997 guidelines and the new draft guidance attempt to address potential ambiguities, but they take different approaches. The older document relies heavily on flowcharts, guiding a manufacturer to a decision about whether to submit a 510(k) by presenting a series of “yes” or “no” questions about the modification that has been made.

The new draft drops the flowchart concept. Instead, it includes a string of case examples to illustrate when different types of changes may trigger the need for a 510(k).

The draft guidance also includes an additional device modification category that is not included in the old guidance: manufacturing process changes. The draft notes that for a device in which manufacturing process information was part of the original 510(k) submission, it is likely that a 510(k) will be needed when the process is changed.

FDA also explains in the manufacturing section that changes to device packaging or to a product expiration date generally do not require a new 510(k). It further gives some technical guidance as to when sterilization process adjustments may merit a new submission.

The other three modification categories addressed in the guidance match the 1997 document: changes to labeling; materials; and technology, engineering and performance.

Both documents emphasize that a single guideline cannot address all potential device changes, and that sometimes it will be necessary for a company to ask FDA reviewers about an individual case. The agency also stresses the importance of companies looking for more advice in any product-specific guidance that may be in force.

More Definitions, Tweaks May Be Sought

“In looking at the 1997 document, we saw a lot of the right principles, but it maybe could have been worded differently, with maybe more emphasis on the regulation itself,” Heather Rosecrans, a device industry consultant with Greenleaf Health, said in an interview. Rosecrans headed CDRH’s 510(k) program from 1992 through the fall of 2010, and thus played a leading role in developing the 1997 guidance and in the early efforts to develop the new draft guidance.

The agency has succeeded on many fronts in the new draft, she said. “I think the document definitely conveys FDA’s view on change or modification. I think it is an accurate portrayal.”

Still, she said, stressing that she had only taken an introductory look at the document, “I am glad that it is a draft. I think there are places that still could use a little bit of work.”

For instance, she cites the much more comprehensive set of definitions included in the 1997 document compared to the draft as a step backwards.

In particular, she points to the more detailed definition for "indication for use" in the older guidance. And she also notes a more detailed discussion, lacking in the new draft, about when a change in indication for use reflects a change in “intended use,” an issue at the heart of determining when a 510(k) is needed and when a device can be considered “substantially equivalent.”

She would also prefer they bring back flowcharts.

“I like the visual of the flowchart,” she said, acknowledging “there are pros and cons.”

She suggested the agency is likely concerned that companies will only look at the flowcharts, without reading the guidance text.

Still, the included case examples will be very useful, she said. Most, if not all, of them are likely based on actual instances in which a company misinterpreted the 1997 guidance, she said.

Impact Of Edwards Controversy

FDA says new guidance is needed in part due to important regulatory changes that have occurred since the 1997 guidance was issued. Most notably, the Quality System Regulation, which governs how companies are supposed to carry out and document design changes, was not implemented until later in 1997 and 1998. Also, the agency points to the need to address rapidly evolving technology changes such as the large increase in software-dependent devices.

But, clearly, the 2008-2009 Edwards Lifesciences controversy was a primary trigger for the effort. The matter attracted attention in Congress, with some, such as Sen. Chuck Grassley, R-Iowa, concerned that the Edwards matter pointed to an inappropriate loophole around 510(k) review.

At the time, several prominent experts, including William Maisel, then a Harvard cardiologist and now deputy director of science at CDRH, recommended that companies should have to notify FDA of all device modifications, whether or not they are likely to warrant a 510(k). (See “ Also see "FDA Policy For Device Modifications Faces Mounting Scrutiny" - Medtech Insight, 6 July, 2009. ” – “The Gray Sheet” July 6, 2009.)

The agency considered the approach of requiring firms to submit periodic modification updates as part its draft 510(k) reform recommendations circulated last year, but elected not to pursue the idea, based in part on a negative response from industry.

“We do recognize that submitting all modifications for all devices could be overly burdensome for us and manufacturers, and might not be necessary to assure that new 510(k)s are submitted when appropriate for modifications to cleared devices,” the agency noted in its January 2011 report announcing near-term 510(k) reform plans. Instead, FDA said it only plans to require regular modification updates, irrespective of 510(k) submission requirements, on a case-by-case basis through device-specific guidance.

The just-issued 510(k) modifications draft guidance, however, was included on the device center’s near-term “action plan” list of 25 reforms, announced in January. And it is the first guidance on the list to be released. (See “ Also see "FDA Kicks Off 510(k) Reform Plan, Punts Some Decisions To IOM" - Medtech Insight, 24 January, 2011. ” – “The Gray Sheet” Jan. 24, 2011.)

How the finalization of the draft guidance will be impacted by the July 29 release of the recommendations by the Institute of Medicine for a broad-scale 510(k) overhaul remains to be seen. (See in this issue, “ Also see "Institute Of Medicine On 510(k) Review Program: Dump It" - Medtech Insight, 1 August, 2011. ” – “The Gray Sheet” Aug. 1, 2011.) Comments on the draft are due Oct. 25.

By David Filmore

FDA Issues 510(k) Modifications Draft Guidance

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