1. Moj Eram, PhD Senior Consultant ARC Experts, LLC 6 April, 2016
Understanding FDA Regulatory Process and Requirements for Medical Device Classification
Moj Eram, PhD Senior Consultant ARC Experts, LLC
6 April, 2016

2. Overview FDA Overview – Regulatory agency Device Classifications
Device Clearance/Approval Requirements
Quality System Regulation (QSR)
Fees and statistics
Summary

3. FDA Structure and Organization – Medical Devices
Office of Medical Product & Tobacco
Center for Drug
Evaluation and Research (CDER)
Center for Device
And Radiological Health (CDRH)
Center for Biologics
Evaluation and Research (CBER)
Center for Tobacco Products
Office of Special Medical Programs

4. What is a Medical Device – FDA Definition
"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."

5. Medical Devices Classification Establishment
FDA is the sole federal agency regulating safety and effectiveness of medical devices.
Most medial devices can be classified using the description of device in Title 21 of the Code of Federal Regulations (CFR), Parts
Approximately 1700 different generic types of devices.
Grouped into 16 medical specialties (i.e. anesthesiology, cardiovascular, neurology, …) – referred to as panels.
These panels make recommendation for device classification.
Each generic types is assigned to one of the three regulatory classes.
Classification is based on risk and level of control necessary to ensure the safety and effectiveness of device.

6. Medical Devices Classification Panels and Regulations1
Clinical Chemistry & Clinical Toxicology Devices
21 CFR 862 2
Hematology and Pathology Devices
21 CFR 864 3
Immunology and Microbiology Devices
21 CFR 866 4
Anesthesiology Devices
21 CFR 868 5
Cardiovascular Devices
21 CFR 870 6
Dental Devices
21 CFR 872 7
Ear, Nose, and Throat Devises
21 CFR 874 8
Gastroenterology and Urology Devices
21 CFR 876 9
General and Plastic Surgery Devices
21 CFR 878 10
General Hospital and Personal Use Devices
21 CFR 880 11
Neurological Devices
21 CFR 882 12
Obstetrical and Gynecology Devices
21 CFR 884 13
Ophthalmic Devices
21 CFR 886 14
Orthopedic Devices
21 CFR 888 15
Physical Medicine Devises
21 CFR 890 16
Radiology Devices
21 CFR 892

7. Risk-Based Classification - Factors may Affect Risk
Design
Devices design should incorporate the principle of inherent Safety.
Manufacturer
Manufacturing processes must well planned and under control.
Validated processes to ensure conforming output and enhance safety.
Intended Use
Objective intent of the manufacturer on how the device will be used.
The indented use will define the Scope of use, and in particular, places where the device is not intended for use.

8. Risk-Based Classification - Factors may Affect Risk
User Experience, Education, and Training
Define the anticipated user.
Identify the expected use’s skill level (home use, hospital use, complex devices).
Device Should not Compromise
The clinical condition and safety of patients.
Consider safety or health of users.
Inherent Risk/Benefit Analysis
The benefit outweighs the risk.

9. What Does it Mean to Classify a Medical Device
Determining the classification is the first step in obtaining FDA clearance/approval for a medical device.
FDA defines the classes on a risk-based approval process into three classes:
Class I – FDA Product Registration
Class II – Pre-Market Notification – 510(k)
Class III – Pre-Market Approval (PMA)
Product development under general and special control based on the class.
Product approval requires a compliant Quality Management System (QMS).

10. Medical Devices Classification – Class I
Class I devices are deemed to be low to moderate risk and are therefore subject to the least regulatory controls (i.e. dental floss, bandages, tongue depressor).
47% of medical devices; 95% exempt form regulatory approval process.
No FDA pre-approval is needed and most are exempt form 510(k) premarket notification.
Must register the device and company with FDA and pay fee.
Under general control.
Quality System Regulations (QSR) - mainly for production control and post market surveillance, record keeping and reporting.

11. Medical Devices Classification – Class II
Class II devices are moderate to high risk and require greater regulatory controls to provide reasonable assurance of the device’s safety and effectiveness (i.e. Blood pressure kit, contact lenses, needles). 
43% of medial devices.
Require Pre-Market Notification (PMN) or 510(k) .
Under general and special control.
Performance data – Bench testing, animal (if needed), clinical (if needed).
Some Class II devices may be exempt from 510(k) clearance.
Formal risk assessment.

12. Medical Devices Classification – Class III
Class III devices are generally the highest risk devices and therefore are subject to the highest level of regulatory control (i.e. replacement heart valves, implantable devices).
Devices that support or sustain human life, are implanted, or present potential unreasonable risk of injury or illness.
Need scientific review and must be approved by FDA before they are marketed.
10% of medical devises.
Formal risk assessment.
Under general/special control and Pre-market approval.

13. FDA Regulatory Approval Process By the Class
~1 month
4-10 Months
36 Months+
Class I
Class III
Class II
Implementation of Quality Management System (QMS) Meeting FDA Quality System Regulation CFR 820 According to the Device Classification Requirements
Device and Company Registration – Subject to FDA Inspection for Compliance
Clinical Trial Development and Approval from FDA
Device may Require Clinical Data
Preparation and Submission of 510(k) Application. Payment of Submission Fee
FDA Review within 90 Days
FDA Issue 510(k) Clearance Letter
PMA Preparation and Submission for FDA for Completeness Review. Payment of PMA fee
Review of Application by FDA
within 180 Days upon Approval
Facility Inspection by FDA
FDA Issues PMA Approval Letter

14. How to Determine Device Classification
Use basic description of the device to perform search – in “Classification Database”.
If the device panel is known for the device, go to the panel, identify the device and corresponding regulation.
Look for a device similar to your device already in the market.
Read product description most similar to your device.
Look for device name, regulation number, submission type, device class, and product code.

15. How to Determine Device Classification - continued
If the device is classified as Class I or II and if It is not exempt, a 510(k) clearance will be required for marketing.
All devices classified as exempt are subject to the limitation on exemption.
Limitation of device exemptions are covered under 21 CFR

16. Device Classification - EXAMPLE
Blood Pressure Cuff - 21 CFR
Identification: A blood pressure cuff is a device that has an inflatable bladder in an inelastic sleeve (cuff) with a mechanism for inflating and deflating the bladder. The cuff is used in conjunction with another deice to determine a subject’s blood pressure.
Classification. Class II (Performance Standard)
Regulatory Medical Specialty: Cardiovascular
Review Panel: Cardiovascular
Product Code: DXQ
Regulation Number:
Submission Type: 510(k)
GMP Exempt: No
FDA Guidance for industry: Non-Automated Sphygmomanometer (Blood Pressure cuff) Guidance – Version 1 – November 19, 1998
Recognized standard: ANSI/AAMI SP10:2002 Manual, Electronic, or Automated Sphygmomanometers

17. Pre-Market Notification – 510(k)
For manufacturers seeking new device approval in the US and for FDA to classify that device.
Using substantial equivalent threshold – predicate device specification, you can demonstrate that your device is as safe and effective as a product(s) legally marketed in the US.
The 510(k) Program: Evaluating Substantial Equivalence in Premarket Notification [510(k)] -
QSR, Labeling, Comparative Information (Clinical Data), Indication for Use, etc.

18. 510(k) Process – Substantial Equivalence (SE)
A 510(k) submission requires demonstration of Substantial Equivalence (SE) to another legally US marketed device. Substantial Equivalence means that the new device is at least as safe and effective as the predicate.
A device is Substantially Equivalent if, in comparison to a predicate it:
Has the same intended use as the predicate; and
Has the same technological characteristics as the predicate, Or
Has the same intended use as the predicate, and
Has different technological characteristics and the information submitted to FDA
Does not raise new or different question of safety and effectiveness; and
Demonstrates that the device is at least as safe and effective as the legally marketed device.

19. 510(k) Process – Substantial Equivalence (SE)
A claim of SE does not mean the new and predicate devices must be identical.
SE is established with respect to:
Intended use,
Design,
Energy used or delivered,
Materials,
Chemical composition,
Manufacturing process,
Performance, safety,
Effectiveness, labeling,
Biocompatibility
Standards, and
Other characteristics, as applicable.

20. A 510(k) is Required When:
Introducing a device into commercial distribution for the first time in the US.
You propose a different intended use for a device which you already have commercial distribution.
The 510(k) regulation 21 CFR 807 specifically requires a 510(k) submission for a major change or modification in intended use.
Most, if not all changes to intended use, will require 510(k).
There is change or modification of a legally marketed device and that change could significantly affect its safety and effectiveness.
Any modifications must be made in accordance with the Quality System Regulations, 21 CFR 820.

21. 510(k) Submission Requirements
Description of the new device
Labeling
Identification of predicate Device(s)
Narrative and tabular comparison
Predicate device’s intended use and indication(s) for Use
Technological characteristic of the device
Principles of operation
Software documentation (If applicable)
Sterility Information (If applicable)
Statement of declaration 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

22. 510(k) Clearance - Decisions
If FDA determines that a device is substantially equivalent to a predicate,
Issue an order granting 510(k) clearance
If FDA determines that a device is NOT substantially equivalent to a predicate, the applicant may:
Resubmit another 510(k) with new data
Request a class I or II designation through the De Novo process
File a reclassification petition; or
Submit a Pre-Market Approval (PMA)

23. Types of 510(k) Submission
Traditional 510(k) –
used for any original 510(k) or modification to a previously cleared device under 510(k). FDA 90 day review.
Special 510(k) –
for modification to a device that has been cleared under the 510(k) process
30-day review by the FDA
relies on risk analysis, declaration of conformity with Design Control (21 CFR ) requirements.
Abbreviated 510(k) –
When a guidance document exist. Relies on declaration of conformance to standards (~ 400 Standards to which can declare conformity).
A special control has been established.
FDA has recognized a relevant consensus standard.

24. Who is Required to submit a 510(k)
Domestic US manufacturers introducing a device to the US market.
Finished device manufacturer
Accessories to finished device
Contract manufacturers are NOT required to submit 510(k)
Specification developers introducing device to the US market
Develop specification for a finished device, but the device is manufactured under contract by another entity
Repackers or relabelers who make significant labeling changes or whose operations significantly affect the device.
Foreign manufacturers/exporters or US representative of foreign manufacturers/exporters introducing a device to the US market.

25. De Novo Classification
FDA will consider De Novos for devices that are not within a device type that has been classified by FD&CA and classified by written notice as “novel”. (EXAMPLE: Esophageal cooling device)
To qualify, the device must be both:
Novel
Low to moderate risk
Two options for De Novo classification:
If receive NSE determination by the FDA in response to a 510(k) submission, within 30 days submit a De Novo Request to make a risk-based evaluation for classification of Class I or II.
If determined there are no legally marketed device (no predicate), may submit a De Novo request risk-based classification of the device into class I or II without submitting 510(k).
Description of the device.
Justification for recommendation for De Novo classification.
Information/data to support the recommendation – Bench, animal, human clinical data.

26. De Novo Review Process FDA has 120 days to review the request.
If FDA classifies the device into class I or II
Special Control guidance issue
Device can be used as predicate for future 510(k) submissions
If FDA determines that the device remains Class III
PMA approval is required for market

27. Pre-Market Approval (PMA) – Class III
No substantial equivalence (SE) found. Must demonstrate safety and effectiveness of a new device by valid scientific evidence.
Convenes an advisory committee, providing nonbinding recommendation to FDA.
Inspection of manufacturer’s facility to QSR.
Safe and effectiveness demonstration
Non-clinical and clinical trial data, device description, intended use claims, manufacturing data, labeling
Investigational Device Exemption (IDE)
Pre-clinical studies, clinical trial protocol approval

28. Pre-Market Approval (PMA) Submission Requirements
Complete description of the device and components (Drawings, photo, etc.)
Detailed description of the methods, facilities, and controls used in manufacturing
Prepared labeling, advertising literature, training materials, etc.
Software documentation (if applicable)
Sterility Information (if applicable)
Biocompatibility information
Extensive clinical trials
Animal studies
Bench testing
Published and unpublished literatures
Bibliography of all published reports concerning device safety and efficacy.

29. Humanitarian Device Exemption (HDE)
Humanitarian Use Device (HUD) are devices for treating or diagnosing a disease or condition that affect fewer than 4000 in the US annually.
Must submit HDE application to FDA.
Similar to PMA requirements, except for effectiveness requirements of PMA.
Application does not require to contain the result of scientifically valid clinical investigations to demonstrate device effectiveness.
Must submit enough information to determine that the device does not pose significant risk of illness or injury.
Only be used after IRB approval for FDA approved indication.
labeling - must state that the device is a HUD, and although it is authorized by Federal Law, the effectiveness of the device for the indication has not been demonstrated.

30. Overview of Medical Device Regulatory Paths
CLASS I
CLASS II
CLASS III
HDE
Probable Benefit Outweighs Risk
APPROVAL TO MARKET DEVICE
510(k)
SE to Predicate?
PMA
Reasonable Assurance of Safety and Efficacy
De Novo 510(k)
No Predicate
CLEARANCE TO MARKET DEVICE
Special Control
General Control
Clinical Data
EXEMPT
Exceed Limits
of Exemption
Yes No
Registration

31. Medical Devices – General Control
General controls are regulatory requirements by FDA, and apply to all medical devices, unless exempt by regulations.
General Control, described in FD&CA Sections 501, 502, 510, 516, 518, 519, & 520, include provisions of the activities pertaining to:
Adulteration
Misbranding
Device Registration and listing
Premarket Notification (510(k))
Banned Devises
Notification, repair, replacement, refund, reimbursement, recall
Records and report
Restricted device
General Provisions including Good Manufacturing Practice (GMP)

32. Medical Devices – Special Control
Special Controls are regulatory requirements for Class II devices, in addition to general controls.
Special controls are device specific and include:
Performance standards – Design Control
Patient registries
Special labeling requirements
Pre-market data requirements
Post-market surveillance
Guidelines/standards

33. Quality System
A medical device quality system is designed to assure that products are safe and effective for their intended use, and
consistently meet the specifications defined by results of clinical and/or detailed technical design and validation.

34. Quality System Regulation (QSR) – 21 CFR 820
Medical device manufacturer must establish and follow a quality systems to help ensure that their products consistently meet applicable requirements and specifications.
QSR also known as current Good Manufacturing Practices (cGMP).
Requirements are not prescriptive, but provide framework of basic requirements for manufacturers to follow.
Place focus on pre and post marketing activities.
Manufacturer must develop a Quality Management System (QMS) commensurate with:
Risk presented by the device
Complexity of device and manufacturing processes
Size and complexity of organization

35. Quality System Regulation (QSR) Elements – 21 CFR 820
Management Controls
Design Controls
Materials Controls
Document Controls
Purchasing Controls
Production and Process Controls
Facilities and Equipment Controls
Document, Record and Change Controls
Corrective and Preventive Action
Labeling Controls
Handling, Storage and Distribution Controls
Servicing Controls
Statistical Techniques

36. Quality System Regulation (QSR) – Design Control – 21 CFR 820.30
Establishing intended use and design input
Design Plan
Deign Review – periodic phase gate reviews of design & development process
Design Verification – Confirmation that Design output conforms to design input
Design Validation – Conformance to the user need and intended use
Design Transfer – Translation of design into manufacturing specifications
Clear and complete documentation of design control process – Design History File (DHF)

37. Integrated Quality Management System (QMS)
Design Control

38. Resources
Code of Federal Regulations (CFR) – 21 Parts 800 to 1299 – Key provisions:
Part Labeling
Part 803 – Medical Device reporting (MDR)
Part 807 – Registration, Listing and 510(k)
Part 812 – IDE
Part 814 – PMA
Part 820 – QSR
Part 822 – Post market surveillance
Part 860 – Classification
FDA, CDRH:

39. User Fees – FY 2016* Application Type Standard Fee
Small Business** Fee
30 Day Notice
$4,182
$2,091
510(k)
$5,228
$2,614
513(g)
$3,529
$1,765
PMA, PDP, PMR, BLA
$261,388
$65,347 *
**Must qualify for SBD.

40. Fee Paying Submissions – FY 2014*
Application Type
FY 2014 Actual
Full Fee Application 25
Small Business 5
510(k)s
3,034
1,037
30-Day Notice
934 91
513(g) 69 31
Establishment Registration
24,026
*Federal Register. Vol 80 (148), Aug. 2015,

41. Summary Start the process of device classification early.
Determine the regulatory path.
Determine quality and control requirements for your device.
Establish communication with FDA to improve the quality of your submission and likelihood of approval.
Develop your product according to the QSR, design control requirements (Class II & III).

42. Thank you
Moj Eram, PhD Senior Consultant ARC Experts, LLC