A year into FDA’s comprehensive 510(k) reform plan, at least one thing is apparent: FDA is setting a new personal best, releasing scores of new guidance documents, standard operating procedures, pilot programs and other initiatives at a breakneck pace.

But what it will all mean for the long-term functioning of the heavily used device review path remains to be seen.

In January 2011, CDRH launched its “plan of action” for enhancing the program, through which most regulated devices enter the market. Based on findings from August 2010 reports on the 510(k) program and on the use of science in regulatory decision making, the action plan set an aggressive pace for the device center in 2011. (See charts.)

And CDRH likely will keep up the pace in 2012 as it reviews comments on the draft guidance documents and other initiatives and finalizes new policies.

“If we step back and look at the 510(k) and science-in-regulatory-decision-making reports and all of the actions that FDA proposed as a result of that, we always thought that represented a large number of recommendations all at once,” Janet Trunzo, executive VP for technology and regulatory affairs at device trade group AdvaMed, said in a Dec. 23 interview. “We were glad to see that FDA had scaled back on those recommendations,” she said, referring to the initial 25-step action plan.

There are early signs that FDA’s efforts are leading to tangible improvements in the timeliness and predictability of the program, CDRH Director Jeffrey Shuren insists.

Nevertheless, “I thought it was a pretty aggressive schedule,” she said.

At this point, it is not clear to many industry watchers whether the myriad planned changes will lead to meaningful improvements.

“Given the number of reforms proposed this year, it is unlikely that either industry or FDA has had the chance to fully consider the impact of their implementation,” Hyman, Phelps & McNamara attorney Jeff Gibbs told “The Gray Sheet.”

But for now, CDRH Director Jeffrey Shuren says there are signs that FDA’s efforts are leading to tangible enhancements in the timeliness and predictability of the program.

“We’re already starting to see some changes in the indicators of performance, although we have a while to go,” Shuren said during a recent device investor meeting.

In a Dec. 27 post on FDA’s new blog for senior leadership, FDA Voice, the center director projected big changes to come.

“As I look back over 2011, I can report that we have made significant progress on the actions we committed to take this year to improve our pre-market programs,” he wrote. “Once these policies and processes are finalized and implemented, we expect to see a significant and positive impact on the pathways to market for medical devices.”

In preparation for year two of FDA’s 510(k) reform initiative, “The Gray Sheet” prepared a rundown of the most significant actions taken in 2011, what’s on deck for 2012 and what 510(k) reform will mean to device makers in the near term.

Key Guidance Docs Released

One of the most potentially influential guidance documents released this year, according to industry, came as a last-minute surprise at the close of 2011. On Dec. 27, FDA issued a long awaited draft guidance entitled “The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)].” (See Also see "Regulatory News In Brief" - Medtech Insight, 2 January, 2012..)

The draft, commonly referred to as the 510(k) paradigm guidance, is meant to clarify when clinical data might be needed in a 510(k), among other topics.

“We are anxiously awaiting several other actions that were planned for this year. … Foremost of those is the 510(k) paradigm guidance,” Trunzo said in the Dec. 23 interview, before the draft guidance was issued.

“Depending on how it is crafted, it could make major changes to the 510(k) program,” Trunzo told “The Gray Sheet.” “What will significantly impact 510(k) reform? The 510(k) paradigm guidance is going to be the one that is most meaningful and most impactful.”

“The 510(k) paradigm guidance is going to be the one that is most meaningful and most impactful” – AdvaMed’s Janet Trunzo

Of the other new draft guidances released as part of FDA’s action plan, the one most troubling to device makers was FDA’s revised policy on when it is necessary to submit a new 510(k) for changes to an already cleared device.

FDA said the 510(k) modifications draft guidance, released July 27, merely clarified existing practices and wasn’t meant to drastically increase the number of 510(k)s submitted for device modifications. Device makers, however, say the new guidelines could double or triple the number of 510(k) submissions for device modifications that FDA receives in a year. (See Also see "A “Disastrous” Draft? Device Firms Take Issue With 510(k) Modifications Guidance" - Medtech Insight, 5 December, 2011..)

The revised guidance, which will replace 1997 guidelines once finalized, no longer includes a flowchart guiding manufacturers to a decision about whether to submit a new 510(k) through a series of “yes” or “no” questions. Instead, the draft contains case examples to illustrate different types of changes that may trigger the need for a 510(k).

Device makers say the new guidance eliminates much of the discretion that device manufacturers previously held to decide whether a change requires a new 510(k). For instance, firms are concerned that they will not be allowed to conduct testing to show that a proposed change does not significantly impact device safety and effectiveness.

“This was one of the low points of proposed ‘reform,’” attorney Gibbs said. “The draft guidance … is likely to result in sponsors needing to submit a new 510(k) for nearly all modifications.”

Also of concern to device makers was FDA’s Aug. 15 draft guidance on designing pivotal clinical trials, which emphasized relying on randomized, blinded trial designs whenever possible. (See Also see "FDA Guidance Emphasizes Randomized, Blinded Trials For PMAs" - Medtech Insight, 22 August, 2011..)

Since the draft guidance was released, FDA has tried to clarify in public forums that randomized, blinded studies may not be appropriate for every device, and that it is open to discussing alternative designs. But firms say they want FDA to add specific language to the final guidance document affirming the validity of alternative trial designs and promoting their use if they are less burdensome.

510(k) Reform: Draft Guidances

In January 2011, CDRH launched its 510(k) reform “plan of action.” Below is a list of relevant draft guidance documents issued in 2011.
Draft Guidance	Description	Date Of Release
510(k) Modifications	Clarifies what changes to a cleared device do or do not warrant submission of a new 510(k), and which modifications are eligible for a Special 510(k).	July 27, 2011
Clinical Trial Designs	Describes acceptable clinical trial designs, and how FDA applies the least burdensome principles.	Aug. 15, 2011
Risk-Benefit Decisions	Clarifies what factors FDA considers when making benefit-risk determinations.	Aug. 15, 2011
De Novo Submissions	Proposes a method for streamlining the de novo classification and review process.	Sept. 30, 2011
Early Feasibility Studies	Clarifies process for starting early feasibility studies, including first-in-man trials.	Nov. 10, 2011
IDE Decisions	Clarifies FDA criteria for approving an IDE application.	Nov. 10, 2011
Evaluating Substantial Equivalence In 510(k)s	Provides clarity on when clinical data might be needed in a 510(k), how a device’s “indications for use” relate to potential changes in its “intended use,” and how to rely on multiple predicates, among multiple other issues.	Dec. 27, 2011
Decision Appeals	Clarifies the process for appealing CDRH decisions.	Dec. 27, 2011
Product Codes	Aid to develop and assign unique product codes more consistently.	Dec. 27, 2011 (announced)

Source: FDA

More Likely To Win A Popularity Contest?

Not all of FDA’s 510(k) reform initiatives met with industry pushback, however.

On Sept. 30, FDA released draft guidance meant to streamline the submission and review process for “de novo” devices, which are low- or moderate-risk products that cannot be found substantially equivalent to any existing 510(k) device on the market. These devices are legally class III products, but do not warrant a lengthy and burdensome PMA review, FDA says.

The new guidance would allow firms to submit a “pre de novo submission” so FDA can analyze earlier whether the device is suitable for the de novo process. If the device is eligible, firms could then submit a 510(k) and de novo petition concurrently, FDA proposes. Through this new pathway, FDA hopes to trim as many as 90 days off the total review process for de novo petitions.

The guidance responded in part to longtime complaints by industry about the inefficiencies of the current de novo process.

“We’re generally supportive of the de novo guidance,” said AdvaMed’s Trunzo, who added that the association soon will submit formal comments on the draft.

Device industry stakeholders also tentatively welcomed two November draft guidance documents and a pilot program aimed at making it easier for companies to begin clinical trials in the U.S.

One draft guidance, on early feasibility studies, aims to streamline the requirements to start and make changes to early-stage clinical studies, including first-in-human trials, which now are often conducted overseas for breakthrough technologies. (See Also see "Jumpstarting U.S. Device Trials? FDA Makes Effort In New Draft Guidelines" - Medtech Insight, 14 November, 2011..)

The second draft guidance, on the investigational device exemption process, offers flexibility in addressing outstanding FDA questions without delaying the start of clinical investigations, FDA says.

“We’re building in a lot more flexibility where now you might be able to start that clinical study even though there’s additional data we need to rely on to make a decision to approve that product,” Shuren said during a Dec. 15 analyst meeting hosted by Wells Fargo Securities. For instance, “There are … opportunities where we may let the study go forward on a staged basis. You may study the first 50 patients and we’re looking at the data coming in and based upon that, may say, ‘Okay, now you can expand it.’”

Other crowd-pleasing initiatives were those to enhance CDRH reviewer training and FDA’s access to external expertise, as well as draft guidance on how FDA weighs the benefits and risks of new devices.

FDA will consider other factors besides safety and effectiveness data alone when reviewing a pre-market submission, such as whether the device is a first-of-a-kind treatment or test, whether it significantly improves patient treatment options and how much risk patients are willing to tolerate, the draft guidance explains. (See Also see "Risk-Benefit Guidance Aims To Improve Pre-Market Review Predictability" - Medtech Insight, 22 August, 2011..)

“The approach there is very patient-centric,” Shuren said of the draft guidance. “The patient is the one who gets the device. Shouldn’t we be considering what a patient is willing to tolerate by way of risk? That is built in there.”

FDA Says Data Shows Improvement

For device makers, the jury is still out on the impact of these planned reforms.

Over the last several years, the percentage of positive 510(k) clearance decisions has decreased, the number of requests for additional information during 510(k) reviews has gone up and total 510(k) review times have lengthened, Shuren acknowledged during the Wells Fargo meeting in New York.

Currently, a 510(k) review takes an average of 146 calendar days, FDA notes.

There were many causes, Shuren said. In some cases, FDA reviewers were asking for data that they did not need to reach a 510(k) clearance decision. In other cases, industry was turning in poor quality submissions that ate up reviewer time.

But he says CDRH has reason to be optimistic going into 2012, and that industry should be, too.

“A few things are now changing in 2011,” the center director noted. The device center is beginning to see a shift in some of the early indicators of performance, he said.

Of significance, 2011 was the first year in which there has been a decrease in the percentage of additional-information letters sent to 510(k) sponsors, Shuren said.

And the percentage of 510(k) clearance decisions, which hit an all-time low in 2010, looks like it pivoted up in 2011, he said.

Additionally, the backlog of 510(k) submissions awaiting decisions at the end of the year is going down. “From 2005 … the backlog has been steadily going up over time until 2010,” Shuren said. “In 2011, it actually dips down.”

“Some of the changes we’re making in the program are actually leading to some better performance,” the center director concluded, though “you’ve not seen that yet in terms of the performance times.”

FDA also has seen improvements on a case-by-case basis, such as times when reviewers took a different approach to balancing risks and benefits when reaching a decision.

“For the moment, it’s a little bit of early indicators and case-by-case stories,” Shuren said. “We think, as we move [into] the coming year, that that will start to translate into more quantitative, more visible improvements.”

Shuren said he hopes these improvements will stem the tide of companies that look first outside the U.S. to develop new device technologies.

“Ultimately we’d like to see folks looking to the U.S. as the first place where they want to bring technology,” he said. “And hopefully, as people start to understand the changes we’re making, where things are going in the program, it’s our hope that maybe we’ve turned the corner and we’re heading toward more optimistic days.”

Wells Fargo Analyst Larry Biegelsen said he came away from the meeting with Shuren and other CDRH leadership encouraged that FDA is “committed to a more timely and predictable regulatory process as well as one that fosters innovation.”

“We would expect to see more tangible progress on review times in 2012,” Biegelsen commented Dec. 16.

510(k) Reform: Pilots, SOPs And More

CDRH’s also announced new pilot programs, standard operating procedures and other procedures as part of its 510(k) reform action plan.
Item	Description	Date
Assurance Case Pilot Program	Started a pilot program to explore the use of “assurance cases” in 510(k) submissions.	March 31, 2011
Center Science Council	Established a center science council and post council charter to FDA website.	March 31, 2011
IDE Program Audit	Characterized the root causes of existing challenges and trends in IDE decision-making.	June 30, 2011
Notice To Industry Letters	Developed SOPs for issuing “notice to industry” letters to more quickly inform stakeholders when CDRH has changed its regulatory expectations based on new scientific information.	June 15, 2011
510(k) Audit & Analysis	Posted 510(k) audit results; determined factors affecting total review time and number of review cycles.	June 15, 2011 & July 19, 2011
Guidance Development SOPs	Developed procedures to provide greater clarity and predictability on the guidance and regulation development process.	July 31, 2011
Reviewer Training	Developed training on core competencies and launched new reviewer certification program.	September 2011
External Experts SOPs	Developed procedures for developing a network of external experts.	Oct. 4, 2011
Additional Information SOPs	Developed procedures to clarify level of sign-off needed for additional data requests in 510(k) reviews.	Nov. 9, 2011
Change In Reviewer SOPs	Developed procedures to improve consistency in pre-market reviews when review staff change during the review.	Dec. 27, 2011

Source: FDA

On Deck For 2012

By the close of 2011, FDA had accomplished the lion’s share of what it set out to do last January.

As of press time, on Dec. 29, the only anticipated guidance documents yet to be announced concerned pre-submissions meetings between FDA and industry, and the use of consensus standards.

According to Shuren, FDA intends to hold pre-submission meetings in a more timely fashion, though requests for pre-submission meetings have doubled over the last five years, he noted.

“We’re working on having [adequate funding from] user fees to have those meetings in a timely fashion,” Shuren said Dec. 15.

The pre-submissions draft guidance will explain that when FDA gives advice in pre-submission meetings, it will document and stand behind that advice, unless there has been a significant change in the submission, or a lot of time has passed between the meeting and the actual submission, Shuren said.

“Companies should be able to rely on [our advice,]” he stressed.

“Pre-submissions are very important to the overall review process,” AdvaMed’s Trunzo said. “We’re anxiously waiting to see what that guidance looks like.”

Another anticipated release in 2012 is the long-awaited proposed rule on unique device identification. For years FDA has struggled to craft a rule that will lay out a scheme for assigning unique codes to nearly all medical devices in order to track them from manufacturing through use. According to FDA’s latest prediction, the proposed rule should have been released sometime in the fall of 2011. (See Also see "Challenges Remain In Linking Unique Device Identifiers To Electronic Health Records" - Medtech Insight, 19 September, 2011..)

“We have been waiting for that one,” Trunzo said. “It will require a lot of new changes for companies of all sizes.”

2012 will also bring to a close a year of negotiations over the cost and terms of the next user fee agreement between FDA and industry. The current fee levels paid by the device industry to support pre-market reviews and other programs will expire at the end of September 2012.

CDRH director Shuren said FDA is continuing to work with industry on a joint package to propose to Congress.

“It’s certainly our hope that we will get there soon,” Shuren said Dec. 15.

The law requires CDRH to present the proposed package to Congress by Jan. 15, though some industry insiders suggest there may be some flexibility on that deadline. If FDA can’t make the deadline, “what happens as of that point is an issue for Congress, but it is our hope that we would have something before that deadline,” Shuren said during the Wells Fargo meeting.

AdvaMed’s Trunzo reiterated Dec. 23 that industry continues to negotiate with FDA and hopes to reach an agreement soon.

A Long, Strange Trip: 510(k) Reform At One Year

More from Regulation

More from Policy & Regulation