This proposal outlines the commercialization pathway for an investigational in vitro diagnostic (IVD) device for nonalcoholic fatty liver disease (NAFLD). They were unable to identify a substantially equivalent predicate device, so they plan to submit a formal pre-submission to the FDA to obtain guidance on the appropriate regulatory pathway. The proposed studies funded by this proposal would support information needed for the pre-submission, including analytical validation and performance characteristics of the test. Depending on FDA feedback, the pathway may involve de novo classification, reclassification, or premarket approval.

1. Excerpt of proposal to the Benaroya Research Institute Commercialization Gap Funding Program
FALL
2013
1. Please outline the development and commercialization pathway and highlight which step(s)
this funding would cover.
After several discussions with Tina Ha and Dr. Lynn Rose, contact with the FDA, and a careful review of numerous
FDA guidance documents we would like to propose the following path toward commercialization of our NAFLD IVD
device. We have determined that this type of test would be classified as a medical device and as such would be
regulated by the FDA Center for Devices and Radiological Health (CDRH) pursuant to Title 21 Code of Federal
Regulations Part 800-1200 (9). There are three FDA classifications for medical devices based upon their level of risk
to the consumer: Class I or Class II are low risk devices, requiring general or special controls, respectively. The
classification of a device determines the level of regulatory control and the pathways for FDA approval of the device;
Premarket Notification (510(k)) (21 CFR 807) for Class I or Class II devices (3) or a Premarket Approval for highest
risk Class III devices (2). If a similar approved device is determined to be “substantially equivalent” (SE) (21 CFR
807.92 (a)) then this device would serve as the “predicate device” and allow for the less stringent Premarket
Notification (510(k)) and Class II determination (10, 11). A device is substantially equivalent if, in comparison to a
predicate it: A) has the same intended use as the predicate; and B) has the same technological characteristics as the
predicate (3). Therefore, we attempted to determine the classification and corresponding regulation of our device,
and searched both the Classification Database (12) and the Classification Panels (13) to find a predicate device
which would permit a 510(k) marketing application. We failed to find a predicate device with both the same intended
use and technological characteristics as our NAFLD IVD device. In fact, we could not identify any device based on
detection of miRNA levels. We did however find a guidance document for similar RT-PCR based gene expression
profiling technology, which we have utilized to design the experiments proposed here that we will need to address in
our marketing application (1). Since we failed to identify a clear predicate device, on the advice of the FDA, we
propose to submit a formal letter to the FDA under the FDA Pre-Submission program (Pre-Sub) (14) to obtain a
formal written response from the FDA providing guidance on the correct marketing application, the need for
prospective clinical studies to support our application and requirement for an Investigational Device Exemption (IDE),
among other information. The Pre-Sub will include detailed information about our IVD including the intended use, risk
analysis, proposed analytical study design, comparator method comparison, specimen information, performance
characteristics, statistical analysis plan, and clinical study protocols. Thus, the information we will obtain from this
funded proposal will be necessary just to submit the Pre-Sub. If based on our Pre-Sub the FDA determines that no
SE exists (they may also require us to submit a 510(k) application prior to making this determination), we will have
the following recourse: A) request a Class I or II designation through the de novo process (15), B) file a
reclassification petition (16), or C) submit a PMA. In addition, there are a number of other regulations that will need to
be addressed for this type of IVD prior to FDA approval. These include: A) a risk assessment (17); B) labeling
requirements (21 CFR 809.10) (18); C) In Vitro Diagnostic Multivariate Index Assays regulation (21 USC 360c(a)(19)
; D) Quality System regulation (21 CFR Part 820)(20); E) Medical Device Reporting regulation (21 CFR Part
803)(21); F) "Registration of Device Establishment" (21 CFR 807.22a) (22); G) documentation of software
development (23); H) Conformance with recognized consensus standards (24). In summary, we have failed to
identify a SE device and will submit a Pre-Sub for further guidance from the FDA. The experiments proposed here
will support our pre-Sub and to some degree any future market application. These experiments include: validation of
the test platform, description of the assay elements, sample collection and handling methods, methods for RNA
extraction, methods for ensuring RNA integrity, reagent components provided or recommended for use, and their
function within the system, instrumentation required for your device, including the components and their function
within the system, types of output generated by the instrumentation and system parameters (e.g., measurement
ranges), the computational path from raw data to the final prognostic result (e.g., how raw signals are converted into
a prognostic signal), internal controls and a description of their specific function in the system, including data
normalization.

2. Excerpt of proposal to the Benaroya Research Institute Commercialization Gap Funding Program
FALL
2013
References and FDA regulations cited
1. Guidance for Industry and FDA Staff - Class II Special Controls Guidance Document: Gene Expression Profiling
Test System for Breast Cancer Prognosis
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm079163.htm
2. Premarket Approval (PMA)
http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions
/premarketapprovalpma/default.htm
3. Premarket Notification (510(k)) submission
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissi
ons/PremarketNotification510k/default.htm
4. Li Y, Kowdley KV. Method for microRNA isolation from clinical serum samples. Anal Biochem. 2012;431(1):69-
75. PMCID: PMC3481852.
5. Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy: a multicentre
retrospective study on 68,276 samples. J Hepatol 1986;2:165-173.
6. https://commonfund.nih.gov/exrna/index.
7. Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, et al. Magnetic resonance
spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population.
Am J Physiol Endocrinol Metab 2005;288:E462-E468
8. (http://www.bioinformatics.babraham.ac.uk/projects/fastqc/).
9. “How To Market Your Device”
http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/default.htm
10. “Substantial Equivalent Device Flowchart” http://www.accessdata.fda.gov/cdrh_docs/reviews/k103039.pdf
11. “How to find a predicate device”
http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions
/premarketnotification510k/ucm134571.htm
12. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm
13. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/ClassifyYourDevice/ucm051530.ht
m
14. Draft Guidance for Industry and FDA Staff Medical Devices: The Pre-Submission Program and Meetings with
FDA Staff
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm310375.htm
15. New Section 513(f)(2) - Evaluation of Automatic Class III Designation, Guidance for Industry and CDRH Staff
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm080195.htm
16. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/ClassifyYourDevice/ucm080412.ht
m
17. 21 CFR 860.7, Determination of safety and effectiveness, in Medical Device Classification Procedures
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=860.7
18. “Device Advice Labeling Requirements for In Vitro Diagnostic Devices."
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/DeviceLabeling/InVitroDiagnosticD
eviceLabelingRequirements/default.htm
19. Class II Special Controls Guidance Document: Instrumentation for Clinical Multiplex Test Systems - Guidance for
Industry and FDA Staff
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm077819.htm
20. http://www.fda.gov/medicaldevices/deviceregulationandguidance/postmarketrequirements/qualitysystemsregulati
ons/default.htm
21. The Medical Device Reporting (MDR) regulation (21 CFR 803)
http://www.fda.gov/medicaldevices/safety/reportaproblem/default.htm
22. Medical Device Establishment Registration and Listing
http://www.fda.gov/medicaldevices/resourcesforyou/industry/ucm314844.htm
23. Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm089543.htm
24. Guidance for Industry and for FDA Staff: Use of Standards in Substantial Equivalence Determinations
http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm073752.htm