De Novo Classification Request - medicaldevicesgroup.net...Diagnostic Devices with nearly identical technological characteristics, but different intended use (i.e., different disease)

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Rob Packard, President

www.MedicalDeviceAcademy.com

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De Novo Classification

Request

No 510(k) Allowed

http://www.medicaldeviceacademy.com/

mailto:[email protected]

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Agenda• A stunning disaster• US FDA Regulatory Pathways• Criteria for 510(k) Clearance• Indications for Use (FDA Form 3881)• Technological Differences• De Novo Submission Options• Example De Novo #1 & #2• Final Rule• De Novo Guidance Documents• 513(g) & Pre-Sub Meetings• RTA Checklists• § 860.224 De Novo request content• Project Planning Tool• Searching Existing Classifications• Benefit-Risk Determination• Human Clinical Studies• Strategic Considerations• Q&A



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Stunning Disasters

1. Wrong pathway. They take the wrong pathway. Say, a 510(k) instead of a De Novo.

2. Wrong test. They spend their money on the wrong tests.

3. Ignored advice. They ignore FDA guidance and/or advice.

https://www.youtube.com/watch?v=Jli_m5zm91g



https://www.youtube.com/watch?v=Jli_m5zm91g

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Device Submission Types

• 510(k) Exempt, Registration & Listing only

• 510(k)

• De Novo Application

• PMA

• Combination Products

• “361 Products”

• Humanitarian Use Device (HUD) Designation



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510(k) Exempt

• No 510(k) Submission Required

• Registration & Listing Only (FY 2020 = $5,236)

• Most Class I & some Class II Devices



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510(k) Submission

• FY 2020 Submission Fee - $11,594 / $2,899

• New Fee for Re-submission after NSE Letter

• No fee for pediatric only submissions

Small Business Status: https://medicaldeviceacademy.com/small-business-qualification-fee-webinar/



https://medicaldeviceacademy.com/small-business-qualification-fee-webinar/

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De Novo Classification Request

• FY 20 Submission Fee - $102,299 / $25,575

• Traditionally was extremely common for In Vitro Diagnostic Devices with nearly identical technological characteristics, but different intended use (i.e., different disease)

• Two Possible Routes:

– Submit after NSE (K number is assigned)

– Initial Submission (DEN number is assigned)





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PMA Submissions

• Clinical Studies Required

• 2+ Years for Modular Submission– 1st Ever submission is free (<$30M)

– FY 2020 FDA Fee $340,995/$85,249

• More rigorous review for approval

• Supplements required for pre-approval of changes

• Pre-approval inspection required

• Time delays are more significant than $https://medicaldeviceacademy.com/small-business-qualification-fee-webinar/




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Criteria for 510(k)

1. Is the predicate device legally marketed in USA?

2. Do the devices have the same intended use?

3. Do the devices have the same technological

characteristics?

4. Do the different technological characteristics raise

different questions of safety and effectiveness?

5. Are the methods of evaluating new/different

characteristics acceptable?

6. Does the data demonstrate substantial

equivalence?



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Where to Download FDA Form 3881

https://www.fda.gov/about-fda/indications-use-pdf-note-best-form-functionality-right-click-3881-link-and-click-save-link-save-your

You need Adobe Acrobat to complete this in a way that you can make changes and save as a PDF.

Otherwise you need to print and scan from Adobe Reader.



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Technological Characteristics

• Materials

• Design

• Energy Source

• Other Features

Raises DIFFERENT issues of safety or effectiveness



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With or Without Previous 510(k)

• Option 1: Any person who receives an NSE determination in response to a 510(k) submission may, within 30 days of receipt of the NSE determination, submit a De Novo request for the FDA to make a risk-based evaluation for classification of the device into Class I or II.

• Option 2: Any person who determines that there is no legally marketed device upon which to base a determination of substantial equivalence may submit a De Novo request for the FDA to make a risk-based classification of the device into Class I or II, without first submitting a 510(k) and receiving an NSE determination.



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De Novo Examples

DEN 100024 – Zap-It!

https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN100024.pdf

DEN 180001 – Idx-DR






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How did Zap-It! get to market?

• Characterization of electrical outputs

• Mechanical durability testing (5,000 uses)

• Biocompatibility – justification provided

• Human performance testing

– 53 subjects, controlled study with sham

– Visual analog scale (VAS)

– 9 follow-up timepoints

– Primary endpoint = Reduction in VAS of 40% @ t=15 min.

– Secondary endpoint = length & width of swelling



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Zap-It! – p < 0.05



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How did IDx-DR get to market?• Breakthrough Device Designation• 10-Site Human Clinical Study• 900 Subject Clinical Study with diabetics (892 completed study)• Experimental: All subjects received IDx-DR result• Control (Masked):

– All subjects had pictures taken with FDA-cleared fundus camera– All images were evaluated by 3 experienced and validated professionals

• Image Quality Results• Precision Study with 24 subjects imaged 10x each (i.e., 240 images)• Human Factors Testing

– Phase 1 - Improve usability– Phase 2 – Develop standardized training materials– Phase 3 – Develop validation test plan– Final testing conducted as part of clinical study

• Validated Training Program – 10 subjects each must be successfully imaged• Protocol for determining when level of change in specifications could significantly

affect safety & effectiveness



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IDx-DR Performance Results

• Sensitivity – 87%

• Specificity – 90%

• PPV (Positive Predictive Value) – 73%

• NPV (Negative Predictive Value) – 96%

• Imageability – 96%

• 99.6% Agreement in Precision Study



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510(k) vs. De Novo TimelineDay 1: FDA receives De Novo Application

By Day 7

FDA sends Acknowledgement LetterORFDA sends Hold Letter if unresolved issues with eCopy

By Day 15

FDA sends Acceptance Review

FDA informs submitter if De Novo Application is accepted for Substantive Review or placed on RTA Hold

By Day 120

FDA grants De Novo



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De Novo Guidance

• Acceptance Review for De Novo Classification Requests - Draft released September 9, 2019– https://www.fda.gov/regulatory-information/search-fda-

guidance-documents/acceptance-review-de-novo-classification-requests

• De Novo Classification Process (Evaluation of Automatic Class III Designation) – Released October 30, 2017– https://www.fda.gov/downloads/MedicalDevices/Device

RegulationandGuidance/GuidanceDocuments/UCM080197.pdf



https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-review-de-novo-classification-requests

https://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM080197.pdf

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Proposed Final Rule for De Novo• Published in the Federal Register on 12/7/18• Comment period ended March 7, 2019• 120 Day Decision Target is based upon existing statute,

but MDUFA IV funding target is 150 days• No requirements for publishing a decision summary

defined• § 860.224 De Novo request format – slightly different• § 860.256 c) FDA may inspect relevant facilities prior to

making De Novo decision– Was Clinical or nonclinical data collected appropriately– Is QMS compliant with 21 CFR 820 – especially for critical

and/or novel manufacturing processes

https://www.federalregister.gov/documents/2018/12/07/2018-26378/medical-device-de-novo-classification-process



https://www.federalregister.gov/documents/2018/12/07/2018-26378/medical-device-de-novo-classification-process

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513(g) Submission

• 2012 Blog - http://medicaldeviceacademy.com/fda-device-classification/

• FDA response within 60 days of receipt

• Standard Fee = $4,603

• Small Business Fee = $2,302

• Non-binding, but can be referenced in submission

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm209841.htm



http://medicaldeviceacademy.com/fda-device-classification/

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm209841.htm

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Pre-Sub Meeting Guidance• The Pre-Submission Program and Meetings with

FDA Staff– Draft guidance issued July 13, 2012– Final guidance issued February 18, 2014– Updated guidance issued September 29, 2017

• Supersedes Pre-IDE Program: Issues and Answers -Blue Book Memo D99-1, dated March 25, 1999

• Usually a one-time meeting rather than iterative• Pre-Subs tracked as “Q Submissions”https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm311176.pdf



https://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm311176.pdf

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Submission Logistics1 eCopy & printed hard copy of the cover letter

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM313794.pdf

FDA officially modified the eCopy requirements to only require a hard copy of the cover letter in 2018.

Cover letter Content:

– Identify submission as “De Novo Application”

– Device Name

– Indications for Use

– Sponsor Contact Info (copy from 510(k) cover letter content)

– Device Category Questions (copy from 510(k) cover letter content)

Address:

U.S. Food and Drug Administration

Center for Devices and Radiological Health

Document Control Center – WO66-G609

10903 New Hampshire Avenue

Silver Spring, MD 20993-0002

DCC = Document Control Center




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Pre-Sub Timeline• RTA Process (0-14 days)

– Does request qualify as a pre-sub?– Is submission sufficiently complete?

• Contact Submitter to schedule date/time of meeting (15-21 days)

• Submit agenda for meeting– allot last 10 minutes to summarizing discussion and action items

• FDA Provides preliminary feedback 5-days prior to the pre-sub meeting (sometimes meeting is cancelled)

• FDA Provides feedback (60-75 days)• Sponsor provides draft minutes to DCC (15 days)• FDA reviews/edits draft meeting minutes (30 days)• May present courtesy copy to reviewer of final meeting

minutes.



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When to have a pre-sub?Earliest TimeWhen you have reviewed and approved your design inputs.

Latest TimeAt design freeze.Before a long-term clinical study.

Examples of good questions for pre-sub meetings are provided in the guidance on pre-sub meetings.



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Integrating Pre-Sub w/

Design & Risk Plans

BeginDHF

Decision

Design Transfer

Pilot Phase Release Phase

HazardIdentification

Risk ControlOption Analysis

Risk Evaluation

RiskEstimation

Risk Control Effectiveness Verification

Risk Management

Plan

RequestPre-SubMeeting

Pre -SubMeeting

BeginDe Novo

SubmitDe Novo

Development PhaseFeasibility PhaseConcept Phase

150+ Days100 Days60-75 Days

RiskManagement

Review

Benefit/RiskAnalysis

Evaluation of Overall Residual Risk

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https://medicaldeviceacademy.com/risk-management-training-webinar/

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Preliminary RTA Questions

1. Is it a combination product?

2. Is the De Novo request with the right center?

3. Is there a Request for Designation (RFD)?

4. Does De Novo for combination product contain same active moiety as an approved drug with exclusivity?

5. Is device type eligible for De Novo?

6. Is there a pending 510(k) or PMA?

7. Is submitter subject to application integrity policy?



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Organizational Elements

1. Table of contents?

2. Sections are labeled?

3. All pages numbered?



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Acceptance Checklist – Appendix A• Intended Use/Indications for Use• Device description• Classification Information & Supporting Data

– Special Controls for Class II?

• Reprocessing/Sterilization• Shelf-life• Biocompatibility• Software• Electrical Safety & EMC• Animal Performance Data (GLP?)• Human Clinical Data• Literature Citations• Benefit-Risk Analysis• Financial Disclosures (FDA Form 3454 and/or 3455)



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Content Checklist – Appendix B

• All content in English

• Trade name identified

• List prior submissions & concerns addressed

• Device Description

• Alternative Practices & Procedures

• Classification Summary• No legally marketed device of same type

• List of potentially similar classification codes

• Rationale for De Novo classification request



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Content Checklist Continued

• Classification Information & Supporting Data– Summary of risks and risk controls

– Executive Summary

– Summary & Full testing Reports

– IVDs – precision/reproducibility, accuracy

• Animal Performance Data

• Human Clinical Performance Data

• Labeling

• Statements, Certifications and Declarations of Conformity



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§ 860.224 De Novo request content1. Table of Contents2. Administrative Information3. Regulatory History4. Device Name5. Indications for Use6. Device Description7. Alternative practices and procedures (Replaces “Review of Efforts to Identify a Predicate”)8. Classification Summary9. Classification Recommendation10. Proposed Special Controls11. Summary of risks and mitigations12. Standards13. Summary of studies14. Benefit Risk Considerations

– Summary of Benefits– Summary of Known Potential Risks to Health– Risk & Mitigation Information– Benefit-Risk Considerations

15. Technical sections16. Other information

– Bibliography of published and unpublished reports not submitted under section 15– Identification, analysis and discussion of other information, data or reports– Copies of reports in bibliography

17. Samples18. Labeling and advertisements19. Other information – submitted by another person, but authorized by requester

Red items are new in the final rule



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Use ToC as Planning Tool

• red = the information does not appear to be available

• yellow = document requires revision and/or reformatting of content

• blue = ready for the client’s review and approval

• green = ready for submission

• Add a column to assign team responsibilities

• Prioritize task completion



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Example of ToC Toolhttps://medicaldeviceacademy.com/510k-project-management-lessons-learned/



https://medicaldeviceacademy.com/510k-project-management-lessons-learned/

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Product Classification Searchhttp://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/classification.cfm



http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/classification.cfm

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Another Search Option

for Product Classifications

1. Identify a device similar to yours

2. Use the registration and listing databasehttp://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRL/rl.cfm

3. Identify the 3-letter product code

4. Click on the code to go to the product

classification page



http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfRL/rl.cfm

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Classification Recommendation

• What makes the device a Class I?

• What makes the device a Class II?

• What makes the device Class I or Class II exempt?

– 471 Device Classifications are Class II with 510(k) exemption (was 274 in 2018)

List of Exempt Devices:http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/315.cfm



http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/315.cfm

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Benefit-Risk Determination• Summary of Benefits

– type of benefits– magnitude of benefits– probability of patients experiencing one or more benefit– duration of beneficial effects

• Summary of Known Potential Risks to Health– Hazard Identification

• Risk Estimation– severity of injuries– type of injuries– number of injuries– frequency of events– probability of events resulting in injury– duration of harmful events– probability of false-positive and false-negatives for diagnostic products

• Risk Controls (i.e., mitigations)• Testing Standards = Design Inputs• Verification of risk control effectiveness

• Benefit-Risk Considerations





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Human Clinical Studies• Non-Significant Risk (NSR) & Significant Risk (SR)• Pre-approved Clinical Study Protocol• Institutional Review Board• Investigational Device Exemption (IDE)• Good Clinical Practices (GCPs)• Informed Consent• Location of Study

– https://www.fda.gov/media/91849/download– https://www.fda.gov/regulatory-information/search-fda-guidance-

documents/acceptance-foreign-clinical-studies-information-sheet

• Statistical Analysis Plan• Statistical Data• Raw Data for any Adverse Events• Financial Disclosures



https://www.fda.gov/media/91849/download

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/acceptance-foreign-clinical-studies-information-sheet

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Strategic Considerations

• Expand Indications Now or Later

• Technological Characteristics & Associated Risks

• Set-up for Future Product Versions

• Special Controls Set Criteria for Future 510(k)s– Which tests offer a competitive advantage to your

company

• De Novo with Clinical Study vs. PMA– 150 Days vs. 2+ Years

– No Supplements vs. Supplement Approvals

– De Novo user fee vs. Free only first 1st Ever Submission



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Rob Packard

[email protected]

+1.802.281.4381

rob13485

Q & A

https://calendly.com/13485cert/30min



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