Open Letter To Office Of Device Evaluation Director Christy Foreman

Followup thoughts and questions

  • Authored by: Mark DuVal
  • Published on: July 22, 2014

July 22, 2014

Christy Foreman
Director Office of Device Evaluation
DHHS/FDA/CDRH/OMPT/CDRH/ODE
U.S. Food and Drug Administration
Center for Devices and Radiological Health
Document Mail Center – WO66-G609
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002

Re: Review of Data in a 510(k), comments to "Draft Guidance for Industry and Food and Drug Administration Staff - The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] (December 27, 2011)," Docket No. FDA-2011-D-0652

Dear Ms. Foreman,

Executive summary

I wanted to follow-up on our telephone last meeting of June 16, 2014, with one of my clients who will remain unnamed in this public document. Let me first thank you for granting us that meeting which we took as a conference call not a face-to-face meeting. As you recall, we tried to explain our position on FDA's review of their 510(k) submission for which an NSE was issued on the grounds it allegedly raised different questions of safety and effectiveness.

It was, in a sense, an awkward call in that my client really meant to raise a general policy issue but it obviously applied specifically to the FDA's review of my client's device. You were kind enough to entertain the meeting and "policy discussion" anyway even though we were using the actual device as our example. To continue that conversation, let me give you some food for thought in examining the way in which I believe 510(k) devices were originally intended to be reviewed by FDA and how, over time, that view has been lost (or possibly unintentionally distorted).

The issue of course is whether FDA in a stage-gated review should look at data submitted by the sponsor in making a determination of whether a device is substantially equivalent (SE) or not. Stated another way, is it acceptable for FDA to make a legal/regulatory determination in a stage-gated review of the SE status without looking at any data?

We know that FDA for decades did not apply "stage-gated reviews" as they are being interpreted and applied by FDA today. As we must, let's start analytically with the statute and regulation. First the statute, "substantial equivalence" means:

...that the device has the same intended use as the predicate device and that the Secretary by order has found that the device-(i) has the same technological characteristics as the predicate device, or (ii) (I) has different technological characteristics and the information submitted that the device is substantially equivalent to the predicate device contains information, including clinical data if deemed necessary by the Secretary, that demonstrates that the device is as safe as a legally marketed device, a nd (II) does not raise different questions of safety and efficacy than the predicate device.

21 U.S. Code § 360-Registration of producers of drugs or device Visit Source

A device is substantially equivalent if, in comparison to a predicate it:

  • has the same intended use as the predicate; and has the same technological characteristics as the predicate; or
  • has the same intended use as the predicate; and has different technological characteristics and the information submitted to FDA;

    • does not raise new questions of safety and effectiveness; and
    • demonstrates that the device is at least as safe and effective as the legally marketed device.
21 U.S. Code § 360-Registration of producers of drugs or device Visit Source

In the normal course of statutory construction, we should really have to go no further t han the direction to look at "the information submitted." The statute and regulation refers to all the information submitted, not some of it , or the amount FDA chooses in its discretion to review. For confirmatory analysis, we can look at the remainder of the statute and regulation (and as a last resort FDA guidance) . The information statute states that the information submitted to FDA must do two things (and both are required) to determine if a device, having different technological characteristics, can remain on the 510(k) pathway, i.e. the "information submitted" must (in the order listed in the statute):

  1. demonstrate that the device is at least as safe and effective as a legally marketed predicated device , and
  2. not raise different questions of safety and effectiveness.
21 U.S. Code § 360-Registration of producers of drugs or device Visit Source

It doesn't say, FDA should do a stage-gated review and determine, on its own without ever looking at data, whether the device meets the statutory definition. Presumably, Congress (and a previous FDA administration creating the implementing regulation) thought that the sponsor's information (including data) would be important to the applying the definition . Congress also listed the two additional items to be reviewed in the order of the reviewing the data first and, presumably, to see if the data raise different questions of safety and efficacy, second. Let's break those constituent elements down.

Analysis

1. Starting with the statute and regulation
Overarching starting point: the mandate is more straightforward than FDA thinks

Congress (and FDA originally interpreting Congress' intent) clearly FDA wanted-first and foremost-to consider the "information submitted to FDA" as part of a holistic two-prong inquiry-that the information submitted-"does not raise new questions of safety and effectiveness; and demonstrates that the device is at least as safe and effective as the legally marketed device."1 There is nothing confusing or unclear about the requirement that FDA must look at the information submitted to it. There is no qualification for the data that mu st be reviewed-it says "the information submitted to FDA." The statute and regulation do not say that the review of the device is to be based upon: "a superficial review or a partial review or a selective review of the information submitted to FDA , to sh ow the device does not raise new questions of safety and effectiveness; and demonstrates that the device is at least as safe and effective as the legally marketed device." It is to be based upon a review of " the information submitted to FDA," without limitation or qualification. So FDA must look at all the information submitted to it in making its determination of whether the new technological characteristic raises different questions of safety and effectiveness and the data support a clearance.

The inquiry is greater and more holistic than FDA is trying to make it out to be. It is tempting and even laudable to think FDA is trying to be administratively efficient and help companies by mercifully making an early call on this issue using the stage-gated approach to avoid reviewing data where FDA deems it unnecessary. FDA's view is that it would rather deliver the bad information earlier, rather than later. But actually FDA is short-changing the applicant and itself, because FDA may actually learn something from the data. Moreover, sponsors are paying for the more thorough review.

The analysis of the statute and regulations really should stop here, because the language is clear and unambiguous, but I've provided some additional policy arguments below.

First prong-"the information submitted " to FDA demonstrates that the device is at least as safe and effective as the legally marketed device

It is interesting that Congress chose this criterion as the first prong. It suggests that Congress intended the second prong (does the device (data) raise issues of safety and efficacy) as subsidiary to the first prong (a review of the data) . I believe this was intentional and, indeed, FDA acted as if it was intentional for decades before it created the "stage-gated" review. FDA wanted a review of the data and if the data revealed different questions of safety and efficacy, the device would not be eligible for the 510(k) path. I also believe that when read in conjunction with Least Burdensome requirements Congress wanted FDA to make determinations in favor of the 510(k) path where necessary and remedy deficiencies through a request for additional data, not by bouncing devices off the 510(k) path through fanciful regulatory interpretation employing a "stage-gated" review. Even if FDA continues to argue it need not consider data submitted to FDA in consideration of the question whether the device raises different question s of saf ety and effectiveness (the second prong), it certainly must do so in consideration of the first prong. Congress used both prongs as conjunctive, not disjunctive, requirements , i.e. both must be considered together. FDA cannot dissociate the two. Remember the statute read s as follows:

...that the device has the same intended use as the predicate device and that the Secretary by order has found that the device:

  1. has the same technological characteristics as the predicate device, or (ii) .
  2. (I) has different technological characteristics and the information submitted that the device is substantially equivalent to the predicate device contains information, including clinical data if deemed necessary by the Secretary, that demonstrates that the device is as safe as a legally marketed device,and (II) does not raise different questions of safety and efficacy than the predicate device..(Emphasis added)
21 U.S. Code § 360-Registration of producers of drugs or device Visit Source

This conjunctive "and" requirement means FDA must also consider whether "the information submitted to FDA... demonstrates that the device is at least as safe and effective as the legally marketed device " after looking at the data. It is not elective. FDA cannot determine if a device is at least as safe and effective as the legally marketed device without looking the data submitted in the application. Clearly data must be reviewed to make this determination. It is unavoidable and inescapable from any construction of the plain meaning of the statute and regulations that FDA must consider all the statutory language in the order and in the context and with the full meaning it was given . It could not be plainer when it states FDA must review "the information submitted."

Second prong-"the information submitted" to FDA does not raise different questions of safety and effectiveness

To determine if a device raises different questions of safety and effectiveness, without the benefit of data, FDA must make that decision in the abstract. That is why Congress wanted the review to first review the data itself and in that data review may reveal different questions (or not). To interpret it in any other way not only does a disservice to sponsor, but the FDA as well. FDA as an organization is normally data-driven, but FDA seems to want to be able to make a judgment call on whether different questions are raised FDA based upon its lone impression, without the benefit of data.

There are three issues with this approach-first it results in FDA guess work; it relies on regulatory intuition and instinct.

This can vary by CDRH divisions and the individuals whom FDA employs-some with vast experience and some quite naive and inexperienced. Even with mature, experienced reviewers, they are not infrequently overt urned by management on such issues. Sometimes they are unaware of facts and data which may change their minds and or give them the comfort level they need 5 DuVal & Associates, PA to conclude a device truly does not raise new questions of safety and effectiveness. FDA is continually trying to improve and make more routine, consistent, predictable and transparent how it makes quality decisions. Would it not be better to require a data-driven agency to review an entire file, routinely, instead of exercising judgment file-by-file and deciding this application should be bounced off the 510(k) path and this one can proceed? FDA should not subject itself to that criticism. And wouldn't FDA benefit from reviewing the data it is given? Without that approach, FDA's current standard fo r review gives individual FDA reviewers , branches and divisions way too much latitude and the opportunity to become arbitrary and capricious.

By allowing a decision to be made without reviewing data gives FDA far too much academic freedom to create issue s where none may exist. If FDA could simply say, with respect to any device, that "it thinks the device is fundamentally different than the predicates and raises new questions of safety and effectiveness, and is therefore ineligible for the 510(k) path," what would ever stand in FDA's way from saying that for any device it did not want cleared as a 510(k) device? How do companies practically refute a "feeling" or intuition? The check on FDA's unbridled discretion, its feeling or intuition, is the standard Congress has provided, i.e. whether the device actually raises a concrete new question of safety and effectiveness. One of the best ways to check FDA's intuition is to require them to consider actual data as part of the 510(k) determination.2

FDA in it's vast repository of institutional knowledge has seen most of the issues before it and FDA knows that often those issues can be tested through existing means or methodology

Further reading:  Draft Guidance for Industry and Food and Drug Administration Staff-The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] (December 27, 2011)

Visit Source

FDA has even attempted to accommodate this approach by allowing for FDA to consider "reference" devices in its review of a 510(k) device.2 This is a good idea. In looking at whether questions are the same or different, FDA is not limited to the predicate device itself, it can look at "reference" devices, a device that serves as precedent for issues seen by FDA before in non-predicate devices. So FDA should employ this knowledge base when reviewing a device instead of attempting to silo its thinking and deliberately shrink its analysis and avert its eyes to avoid looking at the data. It becomes mechanistic and gives the appearance is that FDA is trying to avoid doing its work. This is an issue/perspective (reference devices) with which you and I have seemed to agree over the years.

The system and incentives become skewed when FDA can avoid reviewing a device by engaging in a stage-gated review, avoid doing the heavy lifting of reviewing the data submitted, and then summarily conclude it "raises different questions of safety and effectiveness."

This would lead to FDA obtaining user fees, but never earning them. This is clearly not what Congress intended, either for the standard of review or in enacting user fee legislation.

Finally, under Least Burdensome requirements, the applicant should be given the benefit of the doubt and the data reviewed and the final judgment should err toward allowing a 510(k) path if at all possible

These are Class II moderate risk devices being reviewed (in the vast majority of cases) and as stated above a review of the data may help smooth over FDA concerns and give FDA a comfort level with possible and more tangential "different" issues, so that a device under review may not appear so different to FDA once the data are reviewed. If they were high risk devices with truly novel therapies, it would make sense to take a more cautious approach.

In sum

It is clear Congress wanted FDA to review all the information submitted, not just enough to make a legal/regulatory determination the device does n ot belong on the 510(k) path. In addition, on the first prong of determining whether information submitted to FDA does not raise new questions of safety and effectiveness, FDA must consider the data submitted to it. To avoid doing so relies too much on F DA intuition. Without that approach, it is not a data-driven exercise. It also does not employ FDA's own strength of institutional knowledge and experience and ability to look at reference devices, but sidelines them. The incentives also become skewed a nd if it is not improper, it at least leads to the appearance of impropriety by taking user fees and not earning them through an actual review of data. Finally, Least Burdensome principles would suggest FDA make every effort to help an applicant find stay on the 510(k) path if possible.

2. Moving to the guidance

In the proper sequence of interpretation, one only looks to FDA guidance after it is clear there are or may be ambiguities in the statute or regulations and any guidance must be read to ensure consistency with the plain reading of the statute and regulations. We do not believe such ambiguity exists. Having said that, we believe FDA guidance is consistent with our view as well. If FDA interprets the guidance differently, then its view is inconsistent with the statute and regulations and obviously cannot stand. We should not make the mistake of reviewing the work of the Agency, and forget that the statute trumps any Agency regulation and any regulation trumps guidance.

The narrative of current FDA guidance, depending upon how FDA interprets it, also may actually conflict with the 510(k) flowchart. I believe it directs FDA to review the data. But if FDA interprets that differently, it clearly in contradicts the statute and regulation above. In reviewing the K86-3 Blue Book memorandum, it first starts out with a position that, at first blush, superficially supports FDA's current 3 There is an irony to FDA's practice in stage-gated reviews in which it does not look at the performance data. FDA frequently makes a legal/regulatory determination that the device is NSE and then informs the applicant that the device may qualify for the de novo path. The very statement of saying the device may qualify for the de novo path is a risk-based determination that the device is a likely a Class II device. So if the Agency has looked at the data long enough to determine the device is a candidate fo r the de novo path, why does FDA refuse to use their review of the performance data to determine if the data help them in determining whether the device has a new intended use and/or technological characteristics, and if there are new questions of safety and effectiveness? The Agency should eliminate the practice of stage-gated reviews and get back to reviewing data in every 510(k) review. 7 DuVal & Associates, PA reading of its responsibilities in reviewing 510(k)s, i.e. to do an initial review, but that review is limited to certain circumstances.

FDA's Guidance on the CDRH Premarket Notification Review Program 6/30/86 (K86-3) 510(k) Memorandum #K86-3 that says:

If it is clear from an initial review that a new device has a ...technological feature that makes it NSE, the Center will not review or require performance information in the 510(k). Instead the applicant will be notified that the device is NSE, and any performance data will be reviewed in a PMA or reclassification petition.(Emphasis added)

Guidance on the CDRH Premarket Notification Review Program 6/30/86 (K86-3) Visit Source

I have two thoughts for the Agency on its reading. First, while K86-3 is current and relevant on so many fronts, K86-3 was written at a time when it was heavily disputed whet her any data were needed to demonstrate substantial equivalence. FDA did not intend, and indeed did not use, this phrase in the manner in which FDA is attempting to use it today, i.e. as a gated approach to reviewing 510(k)s. FDA was just stating the obv ious; if it is so clear from an initial review that a device does not belong on the 510(k) pathway because the technological characteristics are so different, FDA sh ould send an NSE letter to the applicant. S t ated another way, I think the Agency at the ti me meant "if it is abundantly clear" from an initial review. As support for this position, the FDA's K86-3 guidance also says: 4

The Center normally will require performance testing data to substantiate equivalence if a new device has an important descriptive difference in comparison to marketed devices within its type, and it is not clea r from an initial review that the device has an intended use or technological change that makes it NSE....

Guidance on the CDRH Premarket Notification Review Program 6/30/86 (K86-3) Visit Source

The word "normally" implies in almost all cases, FDA will require performance data. This creates a presumption that FDA should review the data and not the other way around. In 1986 FDA would avoid looking at da ta and issue an NSE only if it wa s so clear (read: obvious) from an initial (read: superficial) review. So, only obvious calls stemming from a superficial review would qualify for this abbreviated and abrupt treatment , which is so upsetting to industry, i.e. a stage-gated NSE determination . This extreme exception , built into K86-3 , has been turned by FD A today into a standardized stage-gated review which it was clearly never intended to be. That is why FDA's newly-instituted stage-gated approach is so ill-conceived and wrong. It is built upon and erroneous premise and reading of K86-3 and certainly ignores the plain meaning of the statute and regulation which states that FDA must look at "the information submitted to FDA..."

In the case of my client's device, for example, it is not at all "clear" that changing materials would not meet the SE criteria. In fact, it's quite clear that it could meet the SE criteria, if the device passes appropriate testing. This is especially true when FDA has dedicated so much thought to material changes in its past guidance documents. It is abundantly possible that a device with a new material could still raise the same (not different) questions of safety and effectiveness and, moreover, that those differences could be tested through accepted methodologies. How can it possibly be "clear" that any new or different technological characteristic raises different questions and therefore makes the device an automatic NSE-without first reviewing the accepted scientific methods with valid scientific evidence like clinical performance data that assess the effect of the identified technological characteristic? How can an "initial review" without an in-depth review of the data ever be so "clear" that different questions are raised and the submitted scientific and clinical data that could answer the different questions need not be reviewed, evaluated, or considered?

With respect to the material at issue, my client simply substituted one well-known and well-characterized material for another well-known and well-characterized material in this implantable use. In the 510(k) K86-3 Blue Book Memo, FDA provides direction that is instructive for this review, particularly on the issue of new materials. The discussion in the K86-3 Blue Book Memo is right on point in the analysis be ing used for my client's device. The memo states as follows (emphasis added to the quoted section):

If a new device has the same intended use and technological differences, but the technological differences could affect safety or effectiveness, the new device may not be SE. Technological differences may include modifications in design, materials, or energy sources; for example...the use of new materials in orthopedic implants ....The Center finds devices with new technological features to be NSE when the new feature could adversely affect safety or effectiveness in a way that is consequential under the conditions of intended use.(Emphasis added)

In taking this approach, the Center focuses on the technological differences that are medically and scientifically significant and avoids the difficulties that would arise from a mechanistic application of rigid formal criteria to the wide variety of substantial equivalence questions posed by new devices proposed for marketing under a 510(k). Substantial equivalence determinations of necessity require the Center to exercise reasonable scientific judgment. For example, the strict application of a rule that would make device s NSE if they have new material would be inappropriate for such devices as bed pans. For other devices, a "materials rule" may seem more appropriate, e.g. for implants. Even for implants, however, such a rule would be too encompassing if applied to substitute materials known to be, or easily shown to be, equivalent or superior: for example, if applied to a new post-Amendments hip made of titanium, which is generally known to be, and can easily be shown to be, stronger and less corrosive than some stainless steel that was used in pre-Amendments hips.(Emphasis added)

510(k) Blue Book Memo, page 7 5 Visit Source

One thing is clear - the exemption FDA created in K86-3 for devices with data that do not need to be reviewed is where it is abundantly clear (read: obvious) from an initial (read: superficial) review that the device raises different questions of safety and effectiveness. As the guidance also states the "Center will normally require performance testing data" to be reviewed. And to exercise "reasonable scientific judgment" the Agency must look at the scientific information available to it. The Center cannot exercise "reasonable scientific judgment" if the Center is not allowed to review, evaluate, and consider valid scientific evidence a nd/or performance data . The Center should not allow its staff to make a self-proclamation that it has identified questions that allow it to avoid review and consideration of a 510(k) and give the sponsor an NSE decision based on a superficial, definitional "read" of the statutory/ regulatory criteria. If the Center automatically makes a NSE decision, without ever looking at data, that then it has created "a mechanistic application of rigid formal criteria applicable to a wide variety of substantial equivalence questions" that its own guidance says is to trying to avoid.

It cannot be "clear from an initial review" when FDA itself , in the context of implant materials acknowledges that "such a rule would be too encompassing." It would indeed be "a mechanistic application of rigid formal criteria" to avoid looking at data in a 510(k) submission. Data would help, and indeed are necessary for, FDA's review.

Conclusion

 

FDA's current interpretation is 1) not true to either the statute or its promulgated regulation which requires that FDA considers all "the information submitted" to it, and 2) even if one moves to reviewing the guidance, FDA misapplies the original thinking for K86-3. With respect to the statute and regulation, theydo not say that the review of the device is to be based upon a superficial review or a partial review or a selective review of the information submitted to FDA. A review is to be based upon all "the information submitted."I have hesitated going from this simple statutory construction to a review of FDA's guidance out off or concern that the Agency will put more emphasis than is deserved on its own guidance, i.e. its "take" on the Congressional intent. The FDA is far too enamored of its own interpretations in cases where the statutory language is very clear and unambiguous. Guidance (and even regulation) only comes into play if the statute and regulation are unclear.

With that caveat in mind, the guidance still supports this reading. A fair reading of K86-3 (and other guidance documents) and its application of when devices can be summarily dismissed from the 510(k) path is that it is a reserved for extraordinary cases in which"it was clear from an initial review" that the technological characteristics were different. I would suggest this means "abundantly clear." In fact, the guidance states the norm is to require a review of such data. We know that FDA for decades did not apply "stage-gated reviews" as they are being interpreted and applied by FDA today.

Finally, it cannot be clear from "an initial review" that a material change,such as the one my client made, raises different questions to cause an automatic NSE decision. We agree with FDA's previous guidance that such a rule would be "mechanistic" and "all too encompassing" when it comes to changes of materials in implants when those materials are known to FDA. FDA must look at all the information submitted to it in making its determination of whether the new technological characteristic raises different questions of safety and effectiveness and whether the data support a clearance. To not do so is a disservice to the applicant/sponsor and FDA and results in FDA not earning their user fees.

I will submit this memo to the docket for "Draft Guidance for Industry and Food and Drug Administration Staff -The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notifications [510(k)] (December 27, 2011),"since it is not specific to any one client, but to all potential sponsors and represents the thinking of my law firm. My hope is that the thinking in this submission is, hopefully, applied to all 510(k)s and so FDA might reconsider its use of "stage-gated" reviews.

Respectfully submitted,


Mark DuVal
CEO & President
DuVal & Associates, P.A.

Annotation #1

This is the first place in whichthe regulation departs from the strict language of the statute by using the word "new" for the statute's choice of "different" questions of safety and efficacy (not effectiveness—although I believe efficacy and effectiveness are interchangeable).I try to use the word "different" here throughout to maintain consistency with the statute departing only when referring to the regulation and guidance.

Annotation #2

Another concern is with FDA elevating theory over scientific data is that it ignores the hierarchy of the evidence/proof. FDA must ensure the integrity of the 510(k) program and that FDA's decision-making honors the hierarchy of the competing evidence. In many cases the review division brings theory, conjecture or a gut impression to compete in the hierarchy of evidence against hard scientific/medical data submitted by the manufacturer. One can understand if FDA elevates its own theory above that of a company's theory, giving more credibility to FDA's position due to FDA's experience across many devices. But how can theory, even if it is authored by FDA, be elevated over hard evidence, i.e. performance and clinical data? More importantly, how does industry compete with and respond to the review staff's theory, conjecture or a gut impression? This is when industry is completely at the mercy of a fair and impartial (and seemingly omniscient) decision maker in FDA management. Industry can only hope that FDA management can be sympathetic to the review staff's concerns and intuition, but at the end of the day will be data-driven. FDA should not allow a general ephemeral concern or theory to trump hard scientific and medical data.

Annotation #3

There is an irony to FDA’s practice in stage-gated reviews in which it does not look at the performance data. FDA frequently makes a legal/regulatory determination that the device is NSE and then informs the applicant that the device may qualify for the de novopath. The very statement of saying the device may qualify for the de novopath is a risk-based determination that the deviceis a likely a Class II device. So if the Agency has looked at the data long enough to determine the device is a candidate for the de novopath, why does FDA refuse to use their review of the performance data to determine if the data help them in determining whether the device has a new intended use and/or technological characteristics, and if there are new questions of safety and effectiveness? The Agency should eliminate the practice of stage-gated reviews and get back to reviewing data in every 510(k) review.

Annotation #4

The flowchart to the K97-1 guidance supports this narrative by adding the following foot note to the portion of the "Overview" flowchart which reads "Does the Device Have the Same Intended use?" The annotation which clarifies this statement reads: "This Decision is Normally Based Upon Descriptive Information Alone, But Limited Testing Information is Sometimes Required."

In addition, the K97-1 Memorandum has a second more detailed chart which asks "Do the Differences Alter the Intended Therapeutic/Diagnostic/etc. Effect (In Deciding, May Consider Effect on Safety and Effectiveness)."

The annotation which clarifies this statement also allows the reviewer to look at information within and extraneous to the 510(k) application. It reads: "Data may be in the 510(k), other 510(k)s, the Center's Classification Files or the Literature."

Annotation #5

The FDA's K86-3 guidance also says:

"Thus, from a scientific perspective, to determine which technological changes are consequential, the Center considers whether:

  • the new device poses the same type of questions about safety or effectiveness as a predicate device;

  • there are accepted scientific methods for evaluating whether safety or effectiveness has been adversely affected as a result of the use of new technological characteristics; and

  • there are data to demonstrate that new technological characteristics have not diminished safety or effectiveness."

Again the same question: How can the Center ever get, take, or form a scientific perspective or determine if the technological change is consequential or exercise reasonable scientific judgment if it cannot review and consider all the data provided in a 510(k)? According to Question #6 of the 510(k) flowchart if the Center does have questions, the 510(k) submission req uires an automatic NSE decision and such data cannot be reviewed, evaluated, or considered. How can any clinical data gathered OUS or in an IDE ever be submitted to the FDA in a 510(k) since before doing so the device first must not raise different types of safety and effectiveness questions that would be answered by such data?

Annotation #6

FDA review staff frequently state during a review that because the intended use of the two devices are different, FDA is not required to review the non-clinical and/or clinical data from the sponsor to make a SE determination whether the device is SE to t he predicate. The K86-3 Blue Book Memorandum and the Decision Making criteria under the 1998 General/Specific Intended Use guidance clearly contemplates that the Agency will look at literature and data to apply to the analysis of whether new questions of safety and effectiveness are introduced by the new use. Clearly the criteria of "risk," "public health impact," "knowledge base" and "endpoints" within the General/Specific Use guidance calls upon the Agency to look at available data to make those individual decisions and the collective determination of whether the intended use is the same. Looking at those four criteria alone clearly requires FDA to review the data they have been provided as part of the 510(k) review. The answers to these questions are de signed to assist FDA in making the intended use determination. The stage-gated process essentially abandons previous, sound FDA guidance. The applicable criteria are excerpted below:

  • Risk - Does a specific use introduce new risks not normally associated w ith the general use of the device?
  • Public Health Impact - Does a specific use impact public health to a significantly greater degree than the general use of the device? Differences in public health impact can result from changes in target population. These changes may have quantitative dimensions, but routinely will also affect safety and effectiveness because of major qualitative differences in how the device is to be used (e.g. diagnosis vs. screening, cutting soft tissue vs. treating breast cancer).
  • Knowledge base - Is there a body of evidence available to the agency regarding a proposed specific use that reflects existing understanding by the medical community that the more specific use is a subset of the general use, rather than a new intended use? That evidence can be derived from such sources as the medical literature and practice guidelines.
  • Endpoints - To what degree can the performance or clinical endpoints (e.g., ability to ablate tissue; prevention of STDs) used to evaluate the general use be applied to the specific use?

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