Presenter Dr. Joy Frestedt President and CEO Frestedt ... · Project Managers ... “A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is

Presenter Dr. Joy Frestedt

President and CEO Frestedt Incorporated

Contact Information Phone: 952-426-1747 E-mail: [email protected] Website: www.frestedt.com

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Dr. Frestedt is President and CEO of Frestedt Incorporated, a network of over 70 experts and eight highly skilled staff meeting specific needs in regulatory, clinical and quality affairs.

Dr. Frestedt has 30+ years of scientific, clinical and regulatory experience in the health care, pharmaceutical, medical device and food-related industries assisting firms with strategic decisions involving clinical trials, regulatory strategies and the development of quality management systems to compete globally. She has held key positions at the University of Minnesota Academic Health Center, Johnson and Johnson’s Ortho Biotech, Medtronic, Mayo Clinical Trial Services, AstraZeneca Pharmaceuticals and Orphan Medical.

Dr. Frestedt holds a BA in biology from Knox College and a PhD in pathobiology from the University of Minnesota Medical School. She is a member of the American Society of Clinical Oncologists, American Association of Pharmaceutical Scientists, Association of Clinical Research Professionals, Society of Clinical Research Associates and is a Fellow of the Regulatory Affairs Professionals Society.

Dr. Frestedt founded Alimentix, the Minnesota Diet Research Center, was named one of the “100 Most Inspiring People in the Life Sciences Industry” by PharmaVOICE and one of the top 25 “Industry Leaders” a “Women in Business Award” by the Minneapolis/St. Paul Business Journal in 2011.

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www.frestedt.com

www.alimentix.com

Regulatory Affairs Professionals Investigators Research Coordinators Research Associates Project Managers Consultants Educators Administrators

Acknowledgements Thank you to Kristen Evenson and Jess Kessler for helping with this

presentation!

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Getting a medical device cleared for the US market is a cumbersome process. Recent changes have increased the need for clinical trial data in certain significant risk devices previously approved using this regulatory path. This session will describe the 510(k) process to aid the inexperienced clinical research professional understanding the regulatory elements, as well as engage experienced researchers in reviewing ongoing changes the current regulatory climate related to the 510(k) process.

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https://www.socra.org/assets/Annual-Conference/2014-Agendas-Schedules/Agenda-Web-140515.pdf

After the presentation attendees should be able to: ◦ Describe 510(k) process ◦ Differentiate 510(k) types ◦ List 510(k) elements ◦ Understand regulatory documents ◦ Recognize changes in 510(k) process ◦ Know when clinical trial data are needed

5 http://learningworkshop.mindedge.com/2009/11/05/best-practice-five-steps-for-continuous-improvement-learning/

Introduction ◦ History, Purpose, Definitions

Submitting a 510(k) ◦ Regulatory processes ◦ Regulatory timelines

510(k) Elements ◦ 510(k) Paradigm ◦ 510(k) Sections

Changes to the Process ◦ Tips and Challenges

Conclusions ◦ Need for Clinical Data

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http://baltimoreprintstudios.com/2010/05/strategic-plan-posters-are-back/

History Purpose

Definitions

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1820 - First US Standard Drugs List 1906 - Original Food and Drugs Act 1938 - Food, Drug, & Cosmetic Act (FDC) 1976 - Medical Device Amendments Defined device: 201(h) of the Act Manufacturers must register and follow Quality

Control procedures Required risk-based classification - high risk must

have FDA pre-market approval, others must meet performance standards before marketing

Applied safety and effectiveness safeguards to devices

1980 - Investigational Device Exemption 1990 - Safe Medical Devices Act (SMDA) Required facilities to report “serious” incidents Required post market surveillance, device tracking

for implants with potential for “serious” injury 513(i) - Defined Substantial Equivalence 513(a)(1)(B) - Special Controls

1993 - MedWatch launched Revised 1977 policy to excluded women of

childbearing potential from drug studies Guidelines to include both sexes in studies of

drug responses 1994 - Dietary Supplements Health and

Education Act (DSHEA) 1997 - FDA Modernization Act (FDAMA)

Quality System Regulation takes effect Added Exemption for Class I and II Added Least Burdensome Provision Added De Novo designation

1999 - ClinicalTrials.gov founded 2002 - Medical Device User Fee and

Modernization Act (MDUFMA) User fees instituted for devices Office of Combination Products (OCP) formed

2007 – FDA Amendments Act (FDAAA) Reauthorized and expanded MDUFMA

8 http://www.fda.gov/AboutFDA/WhatWeDo/History/Milestones/ucm128305.htm

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http://www.fdaimports.com/blog/fda-by-the-numbers-budget-staff-and-significant-events-since-1930/

Increasing Exponentially?

2014 Budget $4,386,658,000 164% of 2009 (i.e., last 5 years)

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/BudgetReports/UCM394942.pdf

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http://www.fdaimports.com/blog/fda-by-the-numbers-budget-staff-and-significant-events-since-1930/

2014 FTE 15,705 136% of 2009 (i.e., last 5 years) http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/BudgetReports/UCM3949

42.pdf

Type 2008 2009 2010 2011 2012 2013 510(k) 3901 4153 3935 3877 4045 4071

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0

500

1000

1500

2000

2500

3000

3500

4000

4500

2008 2009 2010 2011 2012 2013

510(

k) s

ubm

issi

ons

Year

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/PerformanceReports/UCM384005.pdf

2013 MDUFA Progress Report (2008-2013 Mean: 3982) No Change over last 5 years

2011 - Institute of Medicine issued report “the current 510(k) process is flawed based on its legislative foundation. Rather than

continuing to modify the 35-year-old 510(k) process… the FDA’s finite resources would be better invested in developing an integrated premarket and postmarket regulatory framework that provides a reasonable assurance of safety and effectiveness throughout the device life cycle.” http://www.nap.edu/catalog.php?record_id=13150

2012 - FDA Safety and Innovation Act (FDASIA) Reauthorized user fees to 2017 Expanded post market surveillance Shortened approval timelines

2013 - FDA released listing of ~25 standards related to improving cybersecurity and interoperability of data in medical devices – 2014 suggests risk based approaches 4071 devices submitted to the CDRH 510(k) process 3020 devices cleared through the CDRH 510(k) process Increasing budget and size of FDA contributes to accelerating pace of new

regulations for medical devices (?exponentially?)

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Two typical routes for authorization to market devices ◦ PMA: Premarket

approval ◦ PMN: Premarket

notification [510(k)]

Before a company can market a new device in the US, the manufacturer must obtain FDA authorization unless device is Exempt

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Certain devices are exempt from 510(k) ◦ FDA lists exempt devices (Class I and II) and limitations So they can focus on “more significant public health issues”

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

◦ FDA has exempted almost all Class I devices from PMN ◦ Registration and Device Listing are still required

Some are also exempted from GMP ◦ Records, Complaints files and Sterility info still required

14 http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpcd/classification.cfm?ID=1183

◦ Not exempt ◦ Not pre-amendment device ◦ No PMA required ◦ Must have a Substantially Equivalent predicate

If no predicate available, must use PMA pathway (or consider “de novo” classification)

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510(k) PMA

More applications ~80% of applications ~20% of applications

Fewer Pages 50-100 pages ~1000 pages

Shorter Approval Time ~ 90 days ~ 180 days

Fewer Clinical Studies ~10% need All need

More Devices Class I and II Class III

Additional ease of the 510(k): •No annual or periodic reports •No product supplements •Labeling and manufacturing changes do not need prior approval 16

Introducing device into US commercial distribution for the first time

Proposing a different use for a marketed device Modifying a marketed device in a manner that could

effect a device’s safety or effectiveness Repacking with labeling changes (relabeling) or

operations affecting the device

Did you know ~80% of all devices in the USA are cleared via the 510(k) Process?

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Manufacturers (domestic and foreign) Specification Developers Re-packagers (Kit Makers) Re-labelers (Original Equipment Manufacturers)

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“Each person who wants to market in the U.S., a Class I, II, and III device intended for human use, for which a Premarket Approval (PMA) is not required, must submit a 510(k) to FDA unless the device is exempt…There is no 510(k) form, however, 21 CFR 807 Subpart E describes requirements for a 510(k) submission. Before marketing a device, each submitter must receive an order, in the form of a letter, from FDA which finds the device to be substantially equivalent (SE) and states that the device can be marketed in the U.S. This order "clears" the device for commercial distribution.” ◦ http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyour

device/premarketsubmissions/premarketnotification510k/default.htm

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Federal Food, Drug, and Cosmetic Act (FD&C Act) ◦ Chapter V: Drugs & Devices ◦ Section 510 TITLE: § 360 - Registration of

producers of drugs or devices ◦ Paragraph (k) Report preceding

introduction of devices into interstate commerce

Also know as “Premarket Notification” or PMN

20 http://www.gpo.gov/fdsys/pkg/USCODE-2010-title21/pdf/USCODE-2010-title21-chap9-subchapV-partA-sec360.pdf

“A 510(k) is a premarket submission made to FDA to demonstrate that the device to be marketed is at least as safe and effective, that is, substantially equivalent, to a legally marketed device (21 CFR 807.92(a)(3)) that is not subject to PMA.”

http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/premarketnotification510k/default.htm

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“…A legally marketed device to which a new device may be compared for a determination regarding substantial equivalence is a device that was legally marketed prior to May 28, 1976, or a device which has been reclassified from class III to class II or I (the predicate), or a device which has been found to be substantially equivalent through the 510(k) premarket notification process;…” o 21 CFR 807.92(a)(3)

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Device on market before enactment date of Medical Devices Amendment of 1976

Reclassified device 510(k) device (already SE to another device)

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http://blogs.ocweekly.com/navelgazing/prosthetic-leg_sapd.jpg

http://www.tapfever.com/wp-content/uploads/2011/05/PegLegBates.jpg

If no predicate is available, must use PMA pathway (or consider “de novo” classification, although I do not recommend the de novo pathway at this time)

Assessment demonstrates new device is at least as safe and effective as predicate legally marketed device (not subject to PMA)

Substantially equivalent (SE) to predicate device IF: ◦ Same intended use/indication for use and

same technological characteristics OR

◦ Same intended use/indication for use and ?different? technological characteristics New information submitted does not raise

new questions about safety and effectiveness/performance

Not Substantially Equivalent (NSE)

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Clinical ◦ Safety and performance

Biological ◦ Biocompatibility, sterilization

Technical ◦ Design records, test results ◦ Product specifications (materials, etc.)

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http://www.medright.org/clinical%20medical%20assistant.html

http://www.coloradomesa.edu/biology/

http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm070627.htm

http://www.bioclinica.com/blog/fda-biosimilar-guidance-expected-lead-more-clinical-trials

Find class I or II device with ◦ same intended use/indication for use AND ◦ same or similar technological characteristics

Places to look ◦ FDA databases and guidance documents ◦ Published literature ◦ Competitor company products ◦ Physicians who use similar products

Then, DO THE TESTING to show equivalence

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Regulatory Process Regulatory Timelines

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Strategy formulation begins long before the preparing for the 510(k) submission

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Stages of Process Design Bench File IDE Verify & Validate

(Clinical Trials) File PMA or 510(k) Market

Years 0.5-2 0.5-2 0.5-1 1-2 0.5-3 varies

Test Population Literature

Lab, Animal, Cadaver Studies

Summary and

Proposal

1-5 Case

Studies 20-100

Indication will be

based on population

tested

varies

Purpose Identify

new products

Assess Safety,

Perform-ance and

Bio- Activity

Ensure testing shows

safety and efficacy

Verify Design

Validate Safety, Efficacy

and Indication For Use

Must be safe and effective

Safety Surveillance

– Long-Term

Discovery and

Ideation

Invention and

Prototyping Pre-

Clinical Clinical Regulatory Decision

Product Launch

Post Market Monitoring

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Traditional

New Device or modification*

Complete submission

(21CFR807)

Abbreviated Use existing FDA

guidance document

Follows established Special

Controls

Follows FDA consensus standards

*Special

Modification* to a previously cleared

510(k) device

Declare conformance with 21 CFR 820 Design Controls without providing data

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Usually Class I or II (PMA for Class III) New technology for marketed devices Changes in Performance and Safety concerns or

characteristics Contents: ◦ Administrative information ◦ Labeling ◦ Performance data

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Must rely on one or more of the following: ◦ FDA-recognized consensus standards ◦ Special controls established by regulation FDA guidance

documents Focus: ◦ Show conformance to standard ◦ Summarize performance data

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Device modifications ◦ no change in indication for use

Includes statement regarding verification and validation were performed ◦ results met acceptance criteria

Manufacturing meets conformance standards Applicant usually owns predicate Focus on design control process for modification

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Confirm Product Classification

Identify Predicate Devices already Cleared

Determine Applicable Standards/Guidance

Prepare ALL Sections of 510(k) application (N~21)

Await FDA review within 90 days (or longer)

Register approved device on FDA website

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• FDA receives 510(k) application Day 1

• FDA sends Acknowledgement Letter OR • FDA sends Hold Letter Day 7

• FDA conducts Acceptance Review • Application accepted for Substantive Review or on RTA Hold Day 15

• FDA conducts Substantive Review Day 60

• FDA communicates Substantive Interaction and decides to proceed with Interactive Review or ask for Additional Info Day 90

• FDA sends final MDUFA Decision Day 100

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As of September 30, 2012

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM329702.pdf

90 Days?

510(k) Paradigm 510(k) Sections

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510(k) Paradigm 1. Modification of your own device?

A. No: Go to Step 2 B. Yes: Is design control process still valid?

i. No: Go to Step 2 ii. Yes: Design validation/conformance assured, file Special 510(k)

2. FDA guidance/special control/recognized standard for device? A. No: File a Traditional 510(k) B. Yes: Guidance / Special control standard used?

i. No: File a Traditional 510(k) ii. Yes: Conformance assured, file an Abbreviated 510(k)

3. FDA assessment: Is it Substantially Equivalent to predicate? A. No: Not Substantially Equivalent (NSE) – file a PMA (Class III) B. Yes: Substantially Equivalent (SE) C. Cannot determine: Additional Information will be requested

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http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080187.htm

A Few Questions to Ask: ◦ Is product a medical device? ◦ What classification is device? ◦ Which device is predicate? ◦ What data are needed? ◦ Is Guidance available?

Document the regulatory pathway!

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Gather FDA forms and data for all Sections Medical Device User Fee Cover Sheet CDRH Premarket Review Submission Cover Sheet Cover Letter Table of Contents 510(k) Acceptance Checklist Statement of Indications for Use 510(k) Summary or Statement Truthful and Accurate Statement Proposed Labeling Specifications (including engineering drawings, etc.) Substantial Equivalence Comparison Performance Data (bench, animal, ?clinical? testing) Sterilization validation (if sterile) All Guidance documents specific to the device type if

any exist

http://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/premarketnotification510k/ucm142651.htm

“an instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is: ◦ recognized in the official National Formulary, or the United

States Pharmacopoeia, or any supplement to them, ◦ intended for use in the diagnosis of disease or other conditions,

or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or

◦ intended to affect the structure or any function of the body of man or other animals, and which does not achieve any of its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes."

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http://www.fda.gov/aboutfda/transparency/basics/ucm211822.htm

Three devices classes: Primarily Class I and II may use 510(k) pathway

Class I - General Controls, lowest risk Bandage, irrigation syringe, tongue depressor, reading glasses

Class II - Special Controls, medium risk (not life-sustaining) IV catheters, CT scans, MRI’s, hip/knee joints, surgical mesh Some require clinical trials and post market performance data

Class III - Pre-Market Approval (PMA) usually needed, life supporting and/or has potential risk to patient, documented safety and effectiveness data required

Heart valve, pacemaker, defibrillator, stent, some joint implants Require review of safety and effectiveness before approved

Clinical data may be needed for any class of device.

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Identify relevant similarities and differences in areas such as: ◦ intended use ◦ indications for use ◦ target population ◦ anatomical sites ◦ where used (hospital, home,

ambulance, etc) ◦ energy used and/or delivered ◦ human factors ◦ design ◦ performance; ◦ standards met ◦ materials ◦ biocompatibility ◦ compatibility with the environment

and other devices ◦ sterility

◦ electrical safety ◦ mechanical safety ◦ chemical safety ◦ thermal safety ◦ radiation safety

Discussion should elaborate on similarities identified in table of comparisons and justify differences with supporting rationale and/or data.

Submit labeling for the predicate device(s) to which you are claiming equivalency

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketNotification510k/ucm142651.htm 42

Discuss similarities in predicate comparison table

Description of the new device ◦ Photographs ◦ Engineering drawing

Labeling ◦ Draft promotional

materials Identification of predicate

device(s) Narrative and tabular

comparisons Predicate device’s

intended use, indications Technological

characteristics Principles of operation

Software documentation Sterility information Biocompatibility

information Statement or declarations

of conformance to applicable standards and guidance documents

Summaries of any performance testing

Administrative requirements ◦ Truthfulness and

accuracy statement ◦ 510(k) summary ◦ Payment of a user fee

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510(k) Contents Required by 21 CFR §807 Subpart E

If clinical data provided, Certification of Compliance with ClinicalTrials.gov Data Bank, FDA-3674

If referencing a national/international standard, Standards Data Report for 510(K)s - FDA 3654

If Class III, Class III Certification and Summary (21 CFR 807.94)

Information on sterilization, biocompatibility, expiration date, etc., if applicable.

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http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketNotification510k/ucm134572.htm

Descriptive data ◦ Color, size, weight

Performance testing ◦ Differentiates device from predicate

Clinical Studies ◦ Measures safety and effectiveness

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Test Type Details Product Characterization/Chemistry

Extractable/Leachable

Efficacy/Performance Clinical and Non-Clinical (In vitro and In vivo)

Safety Biocompatibility Microbial Contamination Bioburdens, Microbial IDs, Endotoxins Sterility Sterilization Process Validation;

Product/Biological Indicator Sterility

Package Integrity Package integrity validation- accelerated aging/simulated distribution/seal integrity

Stability Aging/Expiration Clinical Scope/Design/Study Management Compliance Gap Analysis, Risk Assessment; Regulatory

Submission

510(k) Required Test Data

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Specific to type of device - Abbreviated 510(k)???

Submission should detail conformity to the guidance in the submission documents, for example: ◦ Mammography guidance

http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/medicaldevices/medicaldevicesadvisorycommittee/radiologicaldevicespanel/ucm190541.pdf

◦ Solid state X-ray Imaging devices http://www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm073780.htm

◦ Wheelchairs http://www.fda.gov/downloads/medicaldevices/deviceregulationandguidance/guidancedocuments/ucm080560.pdf

Good strategy to use guidance to prepare specific 510(k)

sections as well

◦ For example: Intended Use, Labeling, etc.

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Consider Guidance

What does your device

do? How do you

use it?

Who is the intended patient

population?

◦ Intended Use Determination of Intended

Use for 501(k) devices http://www.fda.gov/medicaldevices/devicere

gulationandguidance/guidancedocuments/ucm082162.htm (1-30-98)

General/Specific http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm073945.pdf (11-4-98)

◦ Must consider indications for predicates

FDA spends time on this section! 48

Unique Device Identifier (UDI)

Product name Sterilization Indications for use Contraindications Warnings Precautions Proper Symbols Disclaimer of liability

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http://www.fda.gov/medicaldevices/deviceregulationandguidance/uniquedeviceidentification/ https://www.premierinc.com/safety/topics/bar_coding/udi.jsp

Must be paid before or at 510(k) submission ◦ All 510(k) types are subject to the User Fee ◦ No user fee for 510(k)s from third-party reviewer ◦ No fee for pediatric devices ◦ Small business ($100M or less) can apply for reduced fee

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/HowtoMarketYourDevice/PremarketSubmissions/PremarketNotification510k/ucm134566.htm

http://www.fda.gov/medicaldevices/resourcesforyou/industry/ucm407660.htm

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Application Type 2014 Standard 2014 Small business 2015 Standard 2015 Small Business 510(k) $5,170 $2,585 $5,018 $2,509 513(g) $3,490 $1,745 $3,387 $1,694 PMA, PDP, PMR, BLA $258,520 $64,630 $250,895 $62,724 panel-track supplement $193,890 $48,473 $188,171 $47,043 180-day supplement $38,778 $9,695 $37,634 $9,409 real-time supplement $18,096 $4,524 $17,563 $4,391 BLA efficacy supplement $258,520 $64,630 $250,895 $62,724 annual report $9,048 $2,262 $8,781 $2,195 30-day notice $4,136 $2,068 $4,014 $2,007

Tips and Challenges

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Have a dedicated writer who understands the product and can write technical and medical documents.

Start by understanding FDA decision-making process - see ◦ “Guidance on the CDRH Premarket Notification Review Program (K86-3)”

Use your resources to understand changes to requirements: ◦ FDA web pages and checklists ◦ FDA recommended format and forms

Prepare/submit complete application and be sure to check for: ◦ logical presentation of data ◦ scientific soundness of tests and data analyses ◦ relevance of the selected test programs to the device and the intended use ◦ completeness of the summary report/s regarding the tests or studies

completed Clear descriptions of tests and results are essential; be sure to

provide reasonable and sufficient details of all test procedures and results; clarifications will be requested and changes suggested

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Cost

Effort

Ti

me

As much as possible, avoid lengthy and possibly

repetitive trials and supporting scientific data ◦ Carefully evaluate/document device changes ◦ Leverage work already completed ◦ Bench, Preclinical and Clinical Testing ◦ Use literature reviews, evidence reports and prior

approval/clearance

Lower cost due to smaller scope and number of

potential studies

Quicker to market due to fewer studies

Lower risk – proven commodity

◦ Existing safety and efficacy information

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Use least burdensome pathway

More products being sent to 513(f)(2) <de novo> for classification determination (new law 7-9-12)

Nearly 1/3 of FDA staff are new and need training ◦ Hiring surges in 2008 and 2009 were problematic!

Increasing difficulty to secure “Substantially Equivalent” rating from FDA

Increasing need for Clinical Data as it seems entire 510(k) program is under review

54 http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080195.htm

<Risk Based Classification> under 513(a)(1) can be requested if no legally marketed predicate is available for SE

Alternatively, for any Not Substantially Equivalent (NSE) determination, device will be automatically routed to Class III and a full PMA with extensive clinical trial data may be required; however, requesting a 513(f)(2) <De Novo classification> within 30 days of NSE determination allows FDA to classify device based on 513(a)(1) within 60 days of request

◦ Automatic Class III designation can be applied when:

No predicate exists Post amendment device is being reclassified New technology is submitted Even when devices are low risk Even when “Special Controls” are used to manage risks

◦ After Not Substantially Equivalent (NSE) determination If cleared, device will be reclassified into Class I or Class II and may be marketed If denied, device remains Class III and cannot be marketed until appropriate submission and clearance

are completed

Also 513(g) Request for Information may be helpful, for example, to determine if 510(k) is required…

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http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/denovo.cfm http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080195.htm

“we found the agency is not doing enough to train new employees...”

“agency has many deficiencies when it comes to managing its workforce.”

FDA is “well aware of these issues” as staff and budgets increase, new responsibilities are added, hiring system is “broken and needs fixing…”

FDA employees care about the mission and “want to be involved in cutting-edge science…” ◦ Per a former Center director: “It’s a thrill,

gives them penache” ◦ BUT is that really the role of an FDA

employee?

56

http://www.washingtonpost.com/r/2010-2019/WashingtonPost/2012/11/19/National-Politics/Graphics/PEW_FDA_Public_19112012.pdf

“The hiring surges in 2008 and 2009 also raised a caution flag…The onboarding for such a significant percentage increase in staff is a challenge… 2010 FDA Profile Age: 47 Salary: $103,529 Tenure: 12 years 28% <3 years Retiring: 14% Note: 1 to 3 years are needed to get newly hired talent up to speed on their jobs...

CDRH review problems are “well known” ◦ “High workloads for reviewers and frequent delays in

processing requests ◦ Spotty staff knowledge of the 510(k) process, resulting in

inconsistent decisions ◦ Inadequate supervision of reviewers ◦ Poor reviewer communication with industry submitters,

particularly in clarifying review standards, expectations and the basis for CDRH decisions

◦ High reviewer attrition rates – double the rates found elsewhere at the FDA”

2011: New reviewer training and certification program ◦ Clear expectations, training roadmap, oversight

57

http://www.washingtonpost.com/r/2010-2019/WashingtonPost/2012/11/19/National-Politics/Graphics/PEW_FDA_Public_19112012.pdf

UCM263385: Analysis of Premarket Review Times Under the 510(k) Program (11-9-11 Last updated) ◦ Medical Device Industry raised concerns about delays ◦ FDA responds: increased delays are “primarily due to

companies taking more time to respond to requests for additional information” ◦ FDA notes the number of “cycles” has increased in both: number of “additional information” AI letters sent AND percentage of submissions receiving AI letters ◦ FDA cites the cause as: “poor quality of submissions”

58 http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhreports/ucm263385.htm

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http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM329702.pdf

SE decisions FELL 15% from 2004-2010 to 73% SE (88-73%) AND

NSE decisions DOUBLED (100% increase from 4-8%)

2012 was still not back to pre 2008 levels…

Hiring surge? Time to clearance increasing

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* 10 months

WOW – TWICE as many need additional info 36-77%

http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhreports/ucm263385.htm http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UCM329702.pdf

COST is staggering!

Is the benefit real?

Inadequate device description ◦ must describe what the drug does to support the intended use

Deficiencies throughout the submission ◦ mostly device description and indications for use must be consistent throughout

submission including cover letter, indications for use form, 510(k) summary, device labeling, etc.

Problems with indications for use ◦ must have same indication as predicate or must not alter the intended use ◦ performance data is based on indication ◦ must identify the predicate and cannot use a PMA device as predicate ◦ if drug is included device indication must be consistent with drug labeling

Failure to follow guidance/standards ◦ must explain why not following

Performance testing was missing ◦ required for all traditional 510(k)s to evaluate if performance is SE to predicate

Clinical data was missing ◦ FDA requires clinical performance data clearly outlined in device specific guidance

61 http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhreports/ucm263385.htm

Sponsor did not address FDA request (e.g., testing will be done is not a sufficient response)

Sponsor raised issues for further follow up (e.g., new test data provided and new questions issued)

FDA raised new question (should have been raised previously)

62 http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhreports/ucm263385.htm

Need for Clinical Data

63

Currently PMAs have an expectation of compliance with GCP and conduct of the trial within the US (but this is less than 15% of device submissions to the FDA)

FDA has a pro-rule suggesting all clinical data should comply with GCP whether in the US or not (if part of 510(k)s, IDE or HDE device submission)

These clinical data requirements would “parallel existing FDA requirements for PMA applications.”

64

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/UCM342236.pdf

“To help manufacturers submit clinical trials that will support rapid approval, CDRH issued draft guidance in August 2011, describing appropriate clinical trial designs to fulfill premarket clinical data requirements.”

This guidance was finalized in November 2013 as “Design Considerations for Pivotal Clinical Investigations for Medical Devices”

◦ Hope to see you at the talk tomorrow on Clinical Data

Needs in US and OUS regulatory submissions

65

http://www.fda.gov/downloads/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/UCM373766.pdf

“Clinical studies are expensive and demand resource-intensive activities that involve a series of steps that need to be clearly understood or planned to meet regulatory requirements. Requiring that clinical studies conducted outside the United States comply with GCP would improve data quality by providing a standardized approach that includes adverse event reporting, sponsor monitoring, and training of study personnel. FDA is unable to quantify the benefits of data quality improvements; however, receipt of higher quality data may influence the likelihood of approval or provide earlier access to novel medical devices.”

66

More clinical data? Universal standards for good clinical and good

data practices for medical device clinical trials to “parallel existing FDA requirements for PMA applications”

67

Introduction ◦ History, Purpose, Definitions

Submitting a 510(k) ◦ Regulatory processes ◦ Regulatory timelines

510(k) Elements ◦ 510(k) Paradigm ◦ 510(k) Sections

Changes to the Process ◦ Tips and Challenges

Conclusions ◦ Need for Clinical Data

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http://baltimoreprintstudios.com/2010/05/strategic-plan-posters-are-back/

Are you able to: ◦ Describe 510(k) process ◦ Differentiate 510(k) types ◦ List 510(k) elements ◦ Understand regulatory documents ◦ Recognize changes in 510(k) process ◦ Know when clinical trial data are needed

69

◦ When you need clinical, regulatory and quality affairs support ◦ We can be “your first call for help”

◦ If you need special clinical trials with foods and NSR devices

◦ Dr. Joy Frestedt, PhD, RAC, CCTI, FRAPS

President and CEO ◦ 612-219-9982

[email protected] www.frestedt.com www.alimentix.com

70

Data supporting discussion about slow review times, increasing FDA staff and budget, CDRH training initiative, and asking for more data…

71

224 243

283

248 261

211

242

301

218

278

224

287

255 249 255 270

241 254

289

0

50

100

150

200

250

300

350

Cleared 510(k)s in 2013 to July 2014

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3020 cleared in 2013 (250/mo)

http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/510kClearances/ucm335382.htm http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceApprovalsandClearances/510kClearances/ucm384564.htm

NOTE: 4071 were submitted in 2013

110 129

140 146

168 176 166 166

020406080

100120140160180200

2006 2007 2008 2009 2010 2011 2012 2013

Cal

enda

r Day

s

Year

FDA Internal Review

73 http://www.emergogroup.com/research/fda-510k-review-times-research

74

http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cdrh/cdrhreports/ucm263385.htm

01-19-09 GAO report: FDA to increase staffing? ◦ 1989, GAO reported FDA lacked resources ◦ 1999-2008, FDA needs medical product oversight staff

Funding and staffing increased 1999-2008 ◦ $562M to $1.2B (>50% increase, industry user fees) ◦ 4,925 to 5,626 FTE (14% increase, all by user fees) ◦ Areas not supported by user fees have less funding FTE funded by user fees 856 to 1,825 (113% increase) FTE by appropriations 4,069 to 3,802 (7% decline)

◦ “FDA could not provide data showing its workload and accomplishments” (e.g., for review of safety issues with medical products). Therefore, “FDA cannot develop complete and reliable estimates of its resource needs…”

◦ FDA did “…not receive enough resources to meet some statutory requirements” (e.g., inspecting certain manufacturing establishments). Therefore, FDA “faces significant challenges fulfilling its mission to oversee the safety and effectiveness of medical products.”

75 http://www.gao.gov/products/GAO-09-581 http://www.gao.gov/assets/300/291336.pdf

GAO Report, 2009 recommended FDA develop an evidence-based estimate of needed resources to fulfill all responsibilities

76

30% more applications 23,079 to 30,060

48% more supplements 13,649 to 20,329

http://www.gao.gov/assets/300/291336.pdf

113% more funding $562M to $1.2B 113% more staff 856 to 1,825 funded by user fees

77 http://www.gao.gov/assets/300/291336.pdf

78

WOW 154% increase from $31M to $78M 2004-2008 (mostly drugs)

AE = adverse event

http://www.gao.gov/assets/300/291336.pdf

FDA developed a tool to estimate resources needed to fulfill its responsibilities and examined future trends likely to affect resource utilization.

This analysis provided FDA with an estimate of resources needed through fiscal year 2015 and supported requests for additional funding, informed Medical Device User Fee Act negotiations, and provided the foundation for implementing new legislation.

79 http://www.gao.gov/assets/300/291336.pdf

80

“…created a whole new set of human resource and leadership challenges” • Training • Management At same time, new responsibilities • Tobacco • Foreign facilities • Food-borne illness

And, cross agency working groups • Knowledge gaps • Staff training • Academic

partners/exchange http://www.washingtonpost.com/r/2010-2019/WashingtonPost/2012/11/19/National-Politics/Graphics/PEW_FDA_Public_19112012.pdf

31% increase: 11,272 to 14,824 employees Permanent: 8,105 to 10,826 (33% increase)

Age: 47 Salary: $103,529 Tenure: 12 years Retiring: 14%

CDRH was formed in 1982 ◦ FDA merged Bureau of Medical Devices and Bureau of

Radiological Health ◦ Mission is to ensure marketed devices are safe and effective

and support innovation 2010, aggressive 3-year strategic workforce plan ◦ Transparency and continuous learning ◦ Dr. Jeffrey Shuren became center director in 2010 ◦ Issued reports in 2010, 2011, 2012, 2013 Responsible for devices throughout lifecycle Clarity with stakeholders about requirements Strengthen workforce and workplace Facilitate innovation (esp. for unmet public health needs)

81

http://www.washingtonpost.com/r/2010-2019/WashingtonPost/2012/11/19/National-Politics/Graphics/PEW_FDA_Public_19112012.pdf

Statement of Jeffrey Shuren, M.D., J.D. ◦ Director, Center for Devices and Radiological Health ◦ Before the Committee on Energy and Commerce, US

House of Representatives Outlines 510(k) Action Plan ◦ new reviewers who need better training ◦ “25 specific actions” FDA will take to improve

predictability, consistency, and transparency of premarket review program including: Developing new/updated guidances Improving communication between FDA and industry Streamlining de novo, clinical trial, IDE processes

82 http://www.hhs.gov/asl/testify/2011/07/t20110720a.html

“…low-risk 510(k) devices without clinical data (80 percent of all devices reviewed each year) came on the market first in the United States as often as or more often than in the EU. The EU typically approves higher- risk devices faster than the United States because, unlike in the United States, the EU does not require the manufacturer to demonstrate that the device actually benefits patients”

“The European Society of Cardiology (ESC) recently issued a “case for reform” of the European medical device regulatory system and their recommendations included creating a unified system, stronger clinical data requirements, and more accountability for notified bodies.”

83 http://www.hhs.gov/asl/testify/2011/07/t20110720a.html

84

Note: The number of submissions/applications includes those received by FDA’s Office of Device Evaluation (ODE) and Office of In-vitro Diagnostics (OIVD). Source: FDA Center for Devices and Radiological Health Research (CDRH). http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/UCM342236.pdf

Significant change in regulations affecting nearly 100-fold more submissions

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For CBER: Nearly 10-fold more submissions

“Notes: Pivotal includes studies involving more than 30 human subjects. Any includes pivotal, feasibility, safety, and pilot studies, and studies with fewer than 30 human subjects. CDRH estimates are based on a sample (n = 342) selected from applications and submissions submitted to CDRH/ODE in fiscal year 2009 which includes all original HDE (n = 3) and PMA (n = 20) applications, and a representative random sample of 510(k) (n = 182) submissions and IDE (n = 137) applications. CDRH estimates do not include applications and submissions to CDRH/OIVD but the omission of CDRH/OIVD data is expected to have no more than a minimal effect on the cost estimates. Total CDRH/ODE sample (n = 342) includes 26 observations where the location of the study was unknown. The CDRH/ODE IDE sample includes only active investigations; incomplete, terminated or withdrawn investigations are not included. Total CBER sample (n=339) includes original submissions/applications for FY2005 through FY2009. NA denotes Not Applicable—CBER did not receive HDE applications during FY2005 through FY2009.

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/UCM342236.pdf

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Type CDRH/ODE Pivotal (%)

CDRH/ODE Any (%)

CBER Pivotal (%)

CBER Any (%)

510(k) 9 14 15 26

HDE 33 100 NA NA

IDE 28 64 20 78

PMA 95 95 100 100

Partnership for Public Service, November 2012 ◦ Cited 2007 report by FDA Science Board Subcommittee FDA’s “scientific workforce does not have sufficient capacity

and capability… to meet current or emerging regulatory responsibilities.”

FDA has “significant gaps in scientific expertise” ◦ Appropriations increased $1.5B in 2007 to 2.5B in 2012 Nearly 60% increase over 5 years (mandated on expanding

the workforce and speeding up the product review process) ◦ User fees increased $597M in 2009 to $1.3B in 2012 2013 user fees projected at $2B for 44% of FDA funding!

87

http://www.washingtonpost.com/r/2010-2019/WashingtonPost/2012/11/19/National-Politics/Graphics/PEW_FDA_Public_19112012.pdf

“The hiring surges in 2008 and 2009 also raised a

caution flag for FDA…The onboarding for such a significant percentage increase in staff is a challenge… special attention should be paid to turnover among new hires… Having made a substantial investment in acquiring new talent, the FDA will want to take whatever steps possible to maximize its return on that investment.” (years of service should be tracked)

Human Resources were being decentralized from HHS in 2010.

88

http://www.washingtonpost.com/r/2010-2019/WashingtonPost/2012/11/19/National-Politics/Graphics/PEW_FDA_Public_19112012.pdf

January 2011 FDA announced a Plan of Action for premarket review of medical devices ◦ “36 specific actions…to increase the predictability, consistency,

transparency, efficiency, and timeliness of device premarket reviews

“The FDA is creating incentive for device developers to conduct their clinical studies first in the U.S.” ◦ Create culture change to greater transparency, interaction,

collaboration, and appropriate balancing of benefits and risks ◦ Assure predictable/consistent recommendations, decision

making, and application of least burdensome principle ◦ Implement efficient processes and use of resources

89 http://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm329008.htm

“The proposed rule will require that clinical studies conducted outside the United States and used to support investigational device exemption (IDE) applications, premarket notification (510(k)) submissions, premarket approval (PMA) applications, humanitarian device exemption (HDE) applications, or product development protocol (PDP) applications comply with good clinical practice (GCP). In addition, the proposed rule seeks to amend the 510(k), HDE and IDE requirements for FDA acceptance of data from clinical studies conducted inside the United States to parallel existing FDA requirements for PMA applications.”

90

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/EconomicAnalyses/UCM342236.pdf

“FDA has not quantified the benefits of the proposed rule which would come from increased collection of information...”

“The current regulations do not address FDA’s acceptance of clinical data to support 510(k) submissions, and HDE and IDE applications...” which make up more than 85% of the applications.

“…IDE applications (including supplements) and 510(k) submissions made up more than 85 percent of the applications (including supplements) and submissions received by FDA’s Center for Devices and Radiological Health (CDRH)...” (however, few of these IDE and 510(k) submissions included clinical data currently)

91