FDA's device center wants to make the 510(k) process more predictable, but one of the first steps to accomplishing this is to break from what CDRH acknowledges are some questionable past decisions, according to a top Office of Device Evaluation official.

In the short term, this means that companies should be wary of relying primarily on past 510(k) clearance requirements or determinations as a regulatory guide.

"If it is not good science and it does not make public health sense, we are not going to worry about contradicting our previous decisions," said Barbara Zimmerman, ODE's deputy director for Premarket Program Management.

Manufacturers often have used regulatory requirements for similar, previously cleared products as a roadmap for future studies and submissions. And to ensure a level playing field, CDRH leaders in the past have been wary of adjusting review standards without formal guidance or rulemaking.

Under FDA's new leadership, however, there is less reverence for prior decisions, Zimmerman said Dec. 9 at the LifeScience Alley annual meeting in Minneapolis.

"I have been in meetings where the argument being made is, 'you did it before; why can't you do it again?' I don't think that is going to be a viable argument in the coming days," Zimmerman said.

"Your argument should be based on the science and the public health's best interest. No matter what the previous decisions were, that should be the case you make, because that is what our leadership is now looking for."

Predictability Is Overarching Goal Of Reform

The shift is one tangible adjustment that has resulted so far from the center's ongoing self-scrutiny, focusing in particular on 510(k)s. Another change is that the center has tightened its ¹ procedures for resolving internal differences of opinion between reviewers and supervisors (² Also see "CDRH Acting Director Jeffrey Shuren Vies For Permanent Spot" - Medtech Insight, 19 October, 2009.).

But with an internal 510(k) working group convening and an Institute of Medicine analysis of the program in the works, more reforms are coming (³ Also see "FDA Asks Institute Of Medicine To Evaluate 510(k) Review Process" - Medtech Insight, 28 September, 2009.).

Ultimately, Zimmerman says, the overarching goal of the efforts is to make the 510(k) process more, not less, predictable.

"Depending at what point in the [510(k)] flow chart you want to take a look at ... whether it is new indications for use, new intended use, new technological characteristics ... you can find an example where we have been inconsistent in the decisions that we have made," she acknowledges.

Precisely how the issue will be addressed remains to be seen.

One organizational reform being batted around by the internal working group is formation of a central group within ODE through which all 510(k) decisions would be filtered in order to make sure that they abide by consistent standards, according to Zimmerman.

The working group is also considering a range of other potential reforms related to how 510(k) reviews work, focusing on nearer-term changes that can be accomplished without the help of Congress. IOM, meanwhile, has a broader mandate to also consider needed legislative changes to the 510(k) standard.

Least Burdensome, Predicate Issues Under Review

FDA has not yet identified the changes that are on the table in any explicit terms. The agency will issue a Federal Register notice soon to schedule a public meeting and provide more details.

One topic being considered by the working group and others in CDRH is the concept of "least burdensome" - the somewhat ambiguous standard of device review codified by the FDA Modernization Act in 1997.

"I think 'least burdensome' is a challenge ... to define and implement," Zimmerman said. "Our committees are considering that. And clearly the agency does want to be least burdensome whenever it can."

But there are limits, she stressed. "For example, if you are asking to do a three-month animal study and FDA asks you to do a six-month study, well, of course, it is less burdensome to do a three-month study, but if we do not think the device is going to fail until six months, that is not scientifically valid."

Further, one subgroup of the 510(k) working group is targeting the issue of how to address new questions of safety and effectiveness that arise from new technologies.

Under the statute, a new device can be judged substantially equivalent to a predicate even if the new device has "different technological characteristics," as long as no new safety and effectiveness issues are raised and the device is at least as safe and effective as the predicate.

This has led to controversy over how different a new product can be and still be judged substantially equivalent, such as in the case of the NeuroStar transcranial magnetic stimulation device for depression, for which the manufacturer attempted to use electroconvulsive shock therapy as a predicate. Ultimately, the device was approved via the de novo process without relying on a predicate (⁴ Also see "Neuronetics Overcomes Negative Panel Review To Earn Clearance For NeuroStar" - Medtech Insight, 13 October, 2008.).

Other points under consideration will likely derive from the conclusions contained in FDA's unprecedented re-assessment of its controversial review for ReGen Biologics' Menaflex knee repair device, which was 510(k)-cleared in December 2008 (⁵ Also see "Internal FDA Menaflex Investigation Finds Serious Process Deviations" - Medtech Insight, 28 September, 2009.).

The September report, an important catalyst for the current reform efforts, cited departures from standard FDA procedures and political pressures as factors tainting the Menaflex review process. But it also pointed to more fundamental ambiguities with 510(k)s that contributed to the troubled review.

The report notes that 510(k) product indications can be too vague to support scientifically valid predicate comparisons; it also says the standard for requesting clinical data to support a 510(k) is unclear.

At the LifeScience Alley meeting, Zimmerman said she thought it was unlikely that the reforms under consideration will lead to more frequent requests from FDA for 510(k) clinical data. But that does not mean companies should not look ahead to increased FDA pre-market challenges.

"Being more consistent does not mean more consistent in what you want; it could be more consistent in what you don't want," she said. "You have to stay a little bit more open-minded."

- David Filmore ( ⁶ d.filmore@elsevier.com )

CDRH To Abandon Bad Precedents On Path To Predictable 510(k)s

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