SIEMENS

March 5, 2010

Division of Dockets Management (HFA-305) Food and Drug Administration 5630 Fishers Lane, Rm. 1061 Rockville, MD 20852

Re: Docket No. FDA-2010-N-0054. Strengthening the Center for Devices and Radiological Health's (CDRH) 510(k) Review Process; Public Meeting; Request for Comments

Dear Sir, Madam,

Siemens Healthcare Diagnostics, Inc., a manufacturer of in vitro diagnostic devices, respectfully submits comments to address the CDRH Task Force questions regarding Strengthening CDRH 510(k) Review Process, as listed in the Federal Register Federal Register : January 27, 2010 (Volume 75, Number 17. Docket No. FDA-2010-N-0054. [See attachment 1] . Siemens appreciates FDA's efforts to identify areas to improve the 510k regulatory review processes .

Siemens Healthcare Diagnostics hopes that you find these comments useful . If you have any questions regarding our comments, please do not hesitate to contact me at 781-269-3401 or by email: noor.malkia-siemens.com

Sincerely,

Noor Malki, M.S . Sr . Manager, Regulatory Affairs 2 Edgewater Drive, Norwood, MA 02493 PHONE : 781-269-3401 noor.malkiO-siemens.com

cc : Cathy Craft, V.P . Regulatory Affairs

F DA 'ac/0 --tii -oas

Siemens HeaIthCare Diagnostics Inc. Page 1 of 1

Sens comments to Docket No. FDA-2010-N-0054 Strengtheni*DRH 510(k) Review Process March 5, 20100'

FDA Docket No. FDA-2010-N-0054 Reference in Jan . 27, 2010 Notice of Public Meetin g

Siemens Comments for FDA _

A. Issues Related to Predicate Devices

1 . FDA maintains a searchable online database to provide interested 1 a and b. The "Decision Summary" which is parties, including prospective 510(k) submitters, with information written by the reviewer is very helpful to about devices that have been cleared for marketing through the 510(k) understanding FDA's expectations on the process . Currently, if a device has been cleared, CDRH's Office of 510(k) . The relevant FDA guidance documents Device Evaluation (ODE) and Office of In-Vitro Diagnostics (OIVD) post or industry standards should be included in the online FDA's "Substantially Equivalent" (SE) letter to the 510(k) Decision Summary. It would also be beneficial submitter with the Indications for Use page for the device, as well as to post the IFU from the submission . This would the 510(k) Summary (written by the 510(k) submitter) or the 510(k) give further information on FDA's expectations Statement for the 510(k) (as specified by 21 CFR 807.93) (see 21 CFR on the labeling . 807.87(h)) . OIVD also posts a "decision summary" (written by FDA reviewers) which includes a summary of submitted data and a The 510(k) database should be expanded with a comparison of the device to the predicate(s) . With respect to the restricted access area (login required) that information described previously, please comment on the following : would allow manufacturer's to view the status of a. How effective is the 510(k) database and search engine in a submission .

helping prospective submitters find and evaluate the adequacy of predicate devices for 510(k) submissions, and write substantial The 510(k) database and search engine is very equivalency rationales? What aspects of the database and search helpful in providing some information necessary engine are useful? What could be improved? What, if anything, should to find and evaluate the adequacy of predicate be added to the 510(k) database and search engine? devices for 510(k) submissions .

b . How effectively do the publicly released documents listed previously describe the cleared indications for use of each device, the The adequacy of the current 510(k) database is technological characteristics of the device, and the methods and type limited by the information that was obtained at of information that were used to determine substantial equivalence to the time of the submission . Earlier devices the device's predicate(s)? If these documents are not sufficient, contain very limited information . In addition, in please describe what additional information or documentation would be the past, information required for submissions useful to interested parties . was not always included in the labeling or the

c. Should FDA require 510(k) holders who receive a substantial summaries for example clinical studies used for

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aens comments to Docket No. FDA-2010-N-0054 Strengtheni*DRH 510(k) Review Process March 5, 2010

FDA Docket No. FDA-2010-N-0054 Reference in Jan. 27, 2010 Notice of Public Meeting

Siemens Comments for FDA

equivalence decision for their device to submit a redacted version of Cancer Markers) . their 510(k) submission after clearance, for public release? Please explain why or why not. Bundled 510k's add a degree of complexity in

2 . Some 510(k) submitters do not accurately portray the reviewing the 510k database. It is difficult to find similarities and differences between the device under review and the instrument 510k's in the current data base . The predicate device(s) . It is unclear whether this problem is due to the name of the device is truncated and often they submitters' lacking complete information about devices that have been are coded by the methods that are submitted cleared previously and may be used as predicates, or whether there with the instrument . Even when reviewing the are other contributing factors . Please comment on this problem and more detailed information, it is not always clear what steps FDA should take to address it . what devices are included .

3 . Generally, a device that has a clearance under the 510(k) process may be used as a predicate, regardless of whether or not the 1 c . We do not believe a redacted version would device is still in use, remains relevant to current standards of care, be helpful since the critical parts of the or has been replaced by new technology. Please comment on the utility submission are likely confidential and thus of this generally inclusive strategy and its positive or negative would be redacted . impact on achieving the two public health goals of the 510(k) program . Should there be stricter criteria for what predicate devices are 2. The information for the similarities and eligible for use in new 510(k) submissions? If so, what criteria should differences is typically gleaned from the be used, and how should those criteria be defined so that they can be predicate device IFU . consistently and effectively applied? Where possible, please also provide specific examples of cases in which the use of an "outdated" 3. No Comment predicate device may have been beneficial or problematic . 4 . Incremental device changes may seem innocuous individually

(i.e ., in one 510(k) submission), but overtime such changes may 4. No comment . accumulate to create a device that is significantly different from the original device (referred to as "predicate creep") . Similarly, clinical non-inferiority studies may be submitted as evidence of substantial equivalence between a device under review and a predicate . When a series of such studies is conducted over time (i .e ., device B is non-inferior to A, device C is non-inferior to B, and device D is non-

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eens comments to Docket No. FDA-2010-N-0054 StrengtheniA*DRH 510(k) Review Process March 5, 201

FDA Docket No. FDA-2010-N-0054 Reference in Jan. 27, 2010 Notice of Public Meeting

Siemens Comments for FDA

inferior to C), the difference in effectiveness between device A and D may approach clinical significance (referred to as "non-inferiority creep") . Please comment on what if any changes should be made to the 510(k) program based on the occurrence of predicate creep and non-inferiority creep . Are there circumstances under which FDA should consider a more thorough review of multiple incremental device changes between 510(k) submissions, or a more thorough review of the appropriateness of clinical non-inferiority studies when assessing 5. Manufacturers need to continue to have the differences in device safety and effectiveness? Please option of choosing multiple predicates . As an explain. example, in the case of IVD devices, a

5 . In some cases, more than one predicate device has been manufacturer may wish to obtain clearance for a submitted by the 510(k) submitter in its evaluation of substantial multi-analyte calibrator . It is quite possible that equivalence . there would not be a single predicate calibrator For example, if there is not a single predicate device that has the that contains the same analytes as the calibrator same indication for use and technological characteristics as the device for which the 510(k) is being filed for. In this under review, a submitter may cite one predicate device in an effort to situation, the use of multiple predicates is the demonstrate the same intended use, and a different predicate device in only option . an effort to demonstrate the same technological characteristics . The use of more than one predicate in this manner, in an effort to demonstrate substantial equivalence, has been referred to as using a split predicate." When a submitter uses a split predicate, the new" device may be very different from any other device on the

market. In other instances, a submitter has used more than one predicate device in the hope that each predicate individually (not combined with the other predicate) supports substantial equivalence . Please comment on whether the use of a split predicate or more than one predicate serves the public health goals of the 510(k) program. If 6a and b. For IVD devices, we believe these possible, please include examples . terms overlap each other and there is not a clear

6. To find that a device is substantially equivalent, FDA must understanding of the differences . Perhaps only determine, among other things, whether or not a new device has the one term should be used . same "intended use" as the predicate device Section 513( i ) of the

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FDA Docket No. FDA-2010-N-0054 Reference in Jan . 27, 2010 Notice of Public Meeting

Siemens Comments for FDA

act) . FDA uses a standardized series of questions, organized into a Further on the overlap of these terms, the flowchart Indications for Use page in a 510(k) is typically (available at http://www.fda .gov/downloads/MedicalDevices/ the same statement that is used in the IVD Device RegulationandGuidance/GuidanceDocuments/UCM081395 .pdf), device IFU under the heading "Intended Use". to guide all 510(k) reviews . Currently, the flowchart distinguishes between an "indication for use" and an "intended use" : A device FDA guidance on the appropriate use of each under review may have a different "indication for use" than the term would be helpful . predicate, yet still be determined to have the same "intended use" and therefore may be found substantially equivalent .

a . Please describe your understanding of an "indication for use" as compared to an "intended use." Please describe what criteria, if any, FDA should use to determine whether or not to consider a different "indication for use" to be a different "intended use." Please provide examples of different "indications for use" that you believe should or should not be considered different "intended uses" and explain your reasoning .

b . What are the advantages and disadvantages of distinguishing between the terms "indication for use" and "intended use" during the review process? What are the advantages and disadvantages of combining these concepts into one term?

B. Issues Related to New Technologies and Scientific Evidence

1 . Section 513(i) of the act defines the term "different 1 . no comment technological characteristics" as "a significant change in the materials, design, energy source, or other features of the device from those of the predicate device." Without regard to the statutory definition, what "other features" should FDA consider (or not consider) to be "different technological characteristics"? If you do not believe an other features should be considered different

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eens comments to Docket No. FDA-2010-N-0054 Strengthenir*DRH 510(k) Review Process March 5, 201

technological characteristics, please state why. 2 . When a 510(k) submitter receives a Not Substantially Equivalent

(NSE) determination from FDA, the submitter may petition FDA, if this type of device has not been approved through the PIVIA process, to classify this new type of device through the Evaluation of Automatic Class III Designation (or de novo) process. FDA may classify such a device as Class I is if the device type is generally of low risk and general controls are determined to be adequate to provide reasonable assurance of safety and effectiveness, or as Class II if special controls can be developed and are adequate, along with general controls, to provide reasonable assurance of safety and effectiveness for the device type . What criteria should FDA use to determine which risks can be mitigated through general controls alone or with special controls, and which risks are sufficient to make the device ineligible for de novo classification?

3. If a device under review has "different technological characteristics" than the predicate(s), it may still be determined to be substantially equivalent if "the information submitted that the device is substantially equivalent to the predicate contains information, including appropriate clinical or scientific data if deemed necessary by the [FDA] * * *, that demonstrates the device is as safe and effective as a legally marketed device and (II) [the device under review] does not raise different questions of safety and effectiveness than the predicate device" (section 513(i) of the act) . How should FDA identify and characterize the risks associated with a new technology that do not raise "different questions of safety and effectiveness?" Are there types of new technology that should not be considered appropriate to be cleared for market through the 510(k) process? Should FDA define "different questions of safety and effectiveness?" If so, please provide suggestions for such a definition .

4 . In some circumstances, FDA may consider data from one of the following four types of comparison studies, or a combination of any of

2. no comment

3. This is more relevant to medical devices other than IVDs - i .e ., when the change in technology may present SAFETY hazards due to direct patient contact .

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eens comments to Docket No. FDA-2010-N-0054 Strengtheni*DRH 510(k) Review Process

them, to determine whether a new device is substantially equivalent to a predicate device : (1) A comparison of specifications to an FDA-recognized standard ; (2) a comparison of specifications through bench testing ; (3) a comparison of specifications through bench and animal or bench and clinical testing ; or (4) a comparison of specifications through bench, animal, and clinical testing .

a . For each particular type of comparison, describe when the comparison is appropriate for a new device .

b . When clinical testing is deemed necessary, such testing is often used to determine whether a device is at least as safe and effective as the predicate (i.e ., no worse than the predicate by a small, clinically insignificant difference called the non-inferiority margin) . If the device is not expected to perform any better than the predicate, then a large sample size may be necessary to show non-inferiority in accordance with the small margin . By contrast, clinical studies conducted to demonstrate superiority to a control, instead of non-inferiority to a predicate, may require a relatively small sample size . Considering that devices under the 510(k) program may represent relatively minor changes compared with a predicate, are there circumstances under which one could show that a device is at least as safe and effective as the predicate without the need to conduct a large non-inferiority study? Please explain . c . The previous comparisons in (2), (3), and (4) each require some

type of testing . Under what circumstances should such testing be performed on the new device alone, and under what circumstances should such testing be performed on the new device in addition to a predicate device as a concurrent comparison? Are there circumstances when a clinical study that does not use the predicate device as the comparator (e.g ., uses a standard of care or a reference method instead) would be appropriate to evaluate substantial equivalence? Please explain .

5 . Some 510(k) submitters do not always initially provide

March 5, 201A

4a. Comparisons for IVD devices are typically done as 1) bench testing or as 2) bench and clinical testing . These types of testing continue to be appropriate for new IVD devices .

b . no comment

c . For IVD devices, typically the only performance study that would involve concurrent predicate testing is the Method Comparison study. Only the new IVD device would be tested for other performance attributes, such as precision, recovery, expected values, interference, sensitivity, etc . Concurrent predicate testing for these attributes is not currently required and we believe they should not be required device .

There are circumstances where the comparator should be the gold standard or a reference method, instead of the predicate device . An example is GCMS for comparing drugs of abuse

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eens comments to Docket No. FDA-2010-N-0054 Strengtheni*DRH 510(k) Review Process

sufficient engineering and design information for their devices under review, to enable FDA to have a sufficient understanding of how the device operates, and whether there are any design issues that would prevent it from operating as intended . Has FDA established sufficiently clear guidelines concerning the provision of such information in 510(k) submissions? If not, what additional guidance might be helpful?

6. Section 513(f)(5) of the act (21 U.S .C . 360c(f)(5)) states that FDA may not withhold an initial classification determination based on "a failure to comply with any provision of the act unrelated to a substantial equivalence decision," including current good manufacturing practice (cGMP) requirements, unless there is a substantial likelihood that such failure will potentially present a serious risk to human health . Would it be beneficial for FDA to have greater authority to withhold an initial classification determination based on a failure to comply with cGMP requirements or other provisions of the act? Please explain .

7 . Currently, some 510(k) submissions include as the "indication for use" a device function that is not associated with a specific clinical utility (e.g ., treatment or diagnosis of a specific condition).

a . For new devices, should a requirement of the 510(k) program be that a device's "indication for use" be proven to FDA to provide clinical utility?

b . Please provide examples of devices whose "indications for use" statements do not describe a clinical utility, and whether this may be beneficial, harmful, or neither . Examples may include devices that are capable of monitoring or measuring a new physiologic parameter that has no standard clinical context, or tool-type devices such as scalpels or lasers that may be cleared to cut and coagulate tissue .

8 . How effective is FDA's current implementation of section 513(i)(1)(E) of the act with respect to curbing off-label use that could cause harm ? The current implementation is described in

test.

March 5, 2010!'

5. No comments as this is not usually applicable to most IVD tests .

6 . no comment

7a. Manufacturer's should not have to prove clinical utility for a Class I or Class II device's indications for use. This would create an uneven playing field for new 510(k) devices, where existing devices are marketed for the same indications .

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aens comments to Docket No. FDA-2010-N-0054 Strengthen il*DRH 510(k) Review Process March 5, 201

"Determination of Intended Use for 510(k) Devices ; Guidance for CDRH Staff (Update to K98-1)" which is available at http ://www.fda.gov/ Medical Devices/DeviceRegulationandGuidance/GuidanceDocuments/ ucm082162htm . Without regard to current law, should FDA consider modifying its approach? Please explain why or why not . If FDA should consider modifying its approach, how should FDA modify it?

8. no comment

C. Issues Related to Practices CDRH has Adopted in Response to a High Volume of 510(k) Submissions

In response to this high volume of work, CDRH has adopted a We believe that the alternative paradigms are not number of practices to allow for less resource-intensive reviews, always applied as described by FDA, for including the third party review program, the Special 510(k) under the example, we have experienced requests for data 510(k) Paradigm, bundling of devices in 510(k) submissions, and when a Special 510(k) submission was filed . This reliance on 510(k) submitters' assertions of conformance to would appear contrary to the intent of the Special recognized standards (as in the Abbreviated 510(k) program) . Due to 510(k) approach and lengthen the review process resource constraints, CDRH often must rely on a single reviewer to for Special 510(k)'s . assess each 510(k) submission . Please comment on the advantages and disadvantages of each of these practices, as related to the The disadvantages to a single reviewer are : 1) quality and timeliness of 510(k) reviews . inconsistent reviews including requests for clinical

data to prove substantial equivalence by some reviewers and not others, 2) potential inexperienced reviews, and 3) completing most of the review and having new issues raised when the review moves up the ladder .

The use of a review team should hopefully reduce the number of requests for additional information and / or reduce the rounds of questions .

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D. Issues Related to Postmarket Surveillance and New Information about Marketed Devices

1 . FDA generally does not require postmarket surveillance studies ! as a condition of medical device 510(k) clearance . Without regard to 1 . no comment - postmarket surveillance studies current law, please comment on whether or not it might be beneficial are not generally applicable to IVDs. However, for FDA to impose such studies as a condition of medical device this might be useful for novel medical devices 510(k) cleared through the 510(k) process . clearance .

2 . Without regard to current law, should FDA allow for the 2. The rescission of a 510(k) clearance decision rescission of 510(k) clearance decisions under a broad range of should be limited to very specific and unique circumstances? If so, what specific criteria might justify the circumstances - for example, where the data rescission of a 510(k) clearance decision? used for the 510(k) submission was grossly

3 . FDA obtains a significant amount of postmarket information for falsified so as to mischaracterize the device . 510(k)-cleared devices, including adverse event reports, recalls, and These circumstances should be treated on a inspectional findings . Without regard to current law, should such case-by-case basis . information influence the premarket 510(k) review of similar devices? If so, how? 3. In specific circumstances (i.e ., the adverse

4. FDA regulations require the submission of proposed labeling events can cause serious injury or death), this (including indications for use, directions for use, precautions, type of postmarket information can be considered warnings, and contraindications) in a 510(k) prior to clearance of a in the review of similar devices . However, some device . However, 510(k) holders sometimes alter the labeling after of this information may be specific to a clearance, so that the final printed labeling is different from that manufacturer (recalls, inspectional findings) and submitted to FDA in the 510(k) . Please comment on whether or not it have little bearing on another manufacturer's might be beneficial for FDA to review and clear the final printed 510(k) . labeling for all 510(k) devices or for selected 510(k) devices prior to marketing . However, this raises challenges including the 5 . FDA does not always know when there has been a purchase, dissemination of information regarding the new

sale, or transfer of ownership of a 510(k) for a particular device . Even "requirements" and the leveling of the playing field though the new owner of the 510(k) is required to register and list, for new players versus the existing 510k holders . FDA may not be aware that the ownership of the 510(k) for the device has legally transferred . Should FDA exercise more authority in this 4 . FDA should not require manufacturer's to area? If so, how? submit final labeling for 510(k) devices . Labeling

changes for a 51O(k) device should be processed

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following the FDA guidance document "Deciding When To Submit a 510(k) for a Change to an Existing Device" .

5 . FDA should be notified of purchases, sales, etc of a 510(k) device and the 510(k) database should be appropriately updated.

General Comments: " The use of guidance documents is valuable only to the extent that it reflects FDA's current thinking . For example, the Drugs

of Abuse guidance issued Dec 2003 is still in draft form and does not reflect FDA's current thinking . Other draft guidances should be finalized as appropriate .

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