Transcript medical device regulation - NIH and VentureWell Sponsored Rowan

FDA Regulation, an Introduction
June 29, 2016
DAVID KUNIN
CONSULTANT
[email protected]
Why does FDA Exist?
John Updike
Prior to FDA
Prior to FDA
Prior to FDA
Dr. Wiley & FDA Poison Squad
1906 Pure Food and Drug Act
After FDA 1970’s
After FDA, 1980’s
Thalidomide Birth Defects
FDA Mission
“Promote and protect public health by helping safe and effective
products reach the market in a timely way, and monitoring products for
continued safety after they are in use. Our work is a blend of law and
science aimed at protecting consumers”.
Office of FDA Commissioner
FDA Divisions and Products

Center for Devices and Radiological Health (CDRH)

Center for Drug Evaluation and Research (CDER)

Center for Biologics Evaluation and Research (CBER)

Center for Veterinary Medicine (CVM)

Center for Food Safety and Applied Nutrition (CFSAN) includes cosmetics

Center for Tobacco Products (CTP)
Types of Medical Devices
Radiation emitting devices - MRI, X-ray, CT, PET, Laser
In Vitro Diagnostic (IVD)
External passive and active
Implant passive and active
Mechanical and electromechanical
Computer controlled
Types of Drugs
Oral (tablet, capsule, sub-lingual, time-release)
Injectable (IV,IM)
 Infusion
Ointment, cream, lotion
Inhalation
Transdermal
Suppository
Drug CFR 314 vs. Device 820.3

Devices primary affect through physical interaction

Drugs primary affect through chemical and metabolic interaction
Biologics
Vaccines
Blood, plasma, blood components
Adult or embryonic stem cells
Donor tissue/cells (bone, skin, cornea, ligaments, tendons,)
Chemically/genetically modified cells (T-cell immunotherapy)
Device Definition CFR 820.3
“Instrument, apparatus, implement, machine, contrivance, implant, in vitro
reagent, or other similar or related article which is intended for use in the
diagnosis or cure of disease or in the mitigation, treatment, or prevention of
disease, in man or animals”
Safety and Effectiveness CFR 860.7

Safety: Use outweighs risks

Effectiveness: Clinically significant results

Valid scientific evidence

Both attributes are statistically based
Combination Products

Combination of two or more regulated products

Devices containing an approved drug or biologic

Drug-Device: antibiotic coated catheter, drug-eluting stent

Biologic-Device: Transfusion, infusion products

Office of Combination Products – fda.gov/combinationproducts
HOW FDA REGULATES DEVICES

PRE-MARKET: Device approval regulations

MANUFACTURING: Quality System regulations

POST-MARKET: Medical Device Reporting regulations
How FDA Regulates Drugs
Abbreviated New Drug Application (ANDA)
New Drug Application (NDA)
Over-the-Counter (OTC)
Prescription (Rx)
Patent Protection Laws
FDA Approval Process

DEVICE – substantial equivalence or pre-market approval (PMA)

DRUGS - abbreviated new drug application (ANDA) or new drug application
(NDA)

BIOLOGICS – biologic license application (BLA)

COSMETICS – no approval required; must use approved color additives and
generally recognized as safe (GRAS) ingredients

FOOD – no approval required; must meet food safety requirements
Device Approval

Pre-Market Notification 510(k): substantial equivalence to approved device

Pre-Market Approval (PMA): no approved device exists, need clinicals
Substantial Equivalence

substantially equivalent to predicate

equivalent characteristics, not identical to predicate

Same intended use as predicate
What FDA Reviews

Design

Manufacturing processes

Performance

Packaging

Sterilization method

Labels (Indications, contraindications, warnings)

Clinical data
Specific Device Requirements

Biocompatibility

Sterility and Pyrogens

Radiopacity

Electrical Safety

Magnetic Resonance Safety

Stability

Connector Safety

Decontamination of Re-usable Devices

Cyber-security
Biocompatibility

Device materials have no deleterious affects on contacting anatomy

Affect on cells, tissues, organs, including blood

25 plus ISO 10993 standards - sensitivity to genotoxicity
Body Contact Categories ISO 10993

Surface: bandage

External Communication: catheter

Implant: pacemaker
Contact Duration ISO 10993

Limited – less than 24 hours

Prolonged – 24 hours to 30 days

Permanent – greater than 30 days
Handout 10993 matrix
Characterize Device Materials

polymers, metals, glass, ceramics, textiles

colorants – pigments/dyes (CFR 21 Parts 73D & 74D)

processing agents – lubricants, mold releases, cleaning agents

joining agents – solvents, adhesives

affect of sterilization agents on device materials

ISO 10993-19: “Physical, Chemical, Morphological, Topographical
Characterization of Materials”.
Sterility

Sterility Assurance Level (SAL): Probability of finding a non-sterile device after
sterilization

FDA requires SAL 10-6
Bioburden

Number/type organisms present on manufacturing surfaces

Number/type organisms present on pre-sterile devices

Factor in selecting sterilization cycle
Bioburden Control

Maintain clean manufacturing surfaces

Equipment, air, water

Test personnel, protective garments

Prepare environmental cleaning and decontamination schedules

Prepare bioburden testing schedules
Sterilization Methods

Ethylene Oxide – ISO 11135

Gamma Radiation and E-Beam – ISO 11137

Autoclave – ISO 17655
Sterilization Considerations

Bioburden

Device materials/density

Material compatibility to sterilants

Packaging materials

Load configuration
Sterility Testing USP 71
 Direct
testing of devices
 Biological
indicators (indirect)
Pyrogens

Microbial endotoxin induces significant febrile response

Control by maintaining low bioburdens

Pyrogen test methods USP <85>
Limulus Polyphemus
Producing LAL Reagents – USP 85
Implant Radiopacity

Capacity of device to be visualized by radiography post-implantation

Radiopacity based on atomic structure of device materials

Stainless steel, titanium are inherently radiopaque

Polymer additives – barium sulfate and titanium oxide

Optical densitometry – NDT (ASTM F640)
Magnetic Resonance Safety

Safety of devices in MRI units

Devices with magnetic properties

Problems – device dislodgement, burns
MRI Safety Labels

SAFE: no contraindications

CONDITIONAL: set MRI limits for power and time

UNSAFE: device unsafe in MRI environment; patient warning bracelet

FDA Guidance: “Establihing Safety and Compatibility of Passive Implants in
an MRI Environment”, 2014.
Electrical Safety
IEC 60601

Power supplies, power cords, circuitry, grounding, shielding

Compatible with hospital power grids and networks

Multiple device compatibility

Environmental compatibility
STABILITY ASTM F1980

Device performs (stable) through-out labeled expiration

Conduct accelerated aging tests ASTM F1980

Arrhenius Model Q10 Rule (time/temperature extrapolation)

Identify negative environments/limits

Temperature, humidity, light, sound, vibration etc.
Connector Safety
DISCONNECTION – ISO 594

Connector design provides secure connection
MISCONNECTION – ISO 80369

Prevent incorrect device connections

Unique connector designs for specific clinical applications

Geometry, color, labels

Gastric, airway, intra-venous connectors
Design of Re-usable Endoscopes

smooth interior and exterior surfaces

can be dis-assembled for cleaning

easy insertion of cleaning instruments

use disposable components where feasible

provide validated decontamination instructions

“Reprocessing Medical Devices in Healthcare Settings” FDA 2015
Cyber-security Design Considerations

network devices (pacemakers, infusion pumps)

programming/re-programming

transmission of data/health-records

FDA “Cyber-security for Medical Devices and Hospital Networks” 2013

FDA “Content of Premarket Submissions for Management of Cybersecurity in Medical Devices” 2014
Software in Computerized Devices

Validate software as integral device component

FDA “General Principles Software Validation”

FDA “Guidance Content Premarket Submissions for Software
Contained in Medical Devices”
Manufacturing Regulations

Quality System Regulations 21 CFR Part 820

820.30 Design regulations critical for safety & effectiveness
Design Requirements

Part 820.30 of QSR

Ten specific design requirements

FDA reviews design files on-site

When complaints are numerous or increasing - MDR
General Design Requirement 820.30(a)

Establish procedures for all design requirements

Adhere to procedures

Document all changes to procedures

Approve changes prior to implementation
Design & Development Planning 820.30(b)

Document all design activities

Accurate & specific

Identify responsibilities by position, not employee name

Review, modify, document changes to plans

Approve/document all changes prior to implementation
Design Input 820.30(c)

Complete intended use – patient, clinician, clinical environment

Device specifications - materials, assembly, testing, sterilization, etc.

Approve input changes prior to implementation
Design Output 820.30(d)

Resulting characteristics from input specifications

Outcome measurements confirm adequacy of inputs

Input/output balance

GI-GO
Input-Output Example
Catheter Extrusion
INPUTS
OUTPUTS
Polymer urethane
chemical analysis
Extrusion time/temperature
tensile and elongation
Gamma irradiation
sterility tests
Design Reviews 820.30(e)

“Documented, systematic examination of design to evaluate adequacy of
design requirements & identify problems”

Conduct & document at appropriate development stages

Include personnel from all applicable departments

Document participants & review date
Design Verification 820.30(f)

Confirmation by examination: output = input

Methods include tests, inspections, FMEA, risk analyses

Acceptance criteria specified

Address non-conformances & document dispositions & CA-PA
Design Validation 820.30(g)

Objective evidence total device conforms with intended uses

Includes interactions with patient, clinician, clinical environment

Verification – objective evidence individual requirements fulfilled

Validation – objective evidence total device conforms to intended use

“Validation greater than sum of Verifications”
Design Transfer – 820.30h

translate design specifications into production specifications

specification changes must be approved, documented, verified, & validated
prior to implementation
Design Changes 820.30(i)

Document

Review

Approve

BEFORE implementation!

Applies to all design changes
Design History File 820.30(j)

Compilation of records describing design history of a finished device

From input through clinicals

Establish/maintain DHF for each type of device (not each device)

DHF contents must be sufficient to adequately describe device design
Procedures, Procedures, Procedures

Establish procedures in clear & specific language

Assure procedures are understood by stakeholders

Strictly adhere to procedural requirements

Approve & document changes prior to implementation

Procedures apply to ALL FDA design control requirements
FDA Labeling Requirements

Any written, printed, graphic, electronic material on/accompanying a device

Includes product package labels, instructions, manuals etc.

Refers to all materials included in submission and approved by FDA

Can information be understood by intended user?

RX or OTC

Patient or clinician
Indications and Contraindications

Indications: intended use

Contraindications: situations or environments to be avoided

Warnings: situations where serious injury or death may occur

Black Box Warning: high probability of death (poisons, cigarettes)
Instructions for Use

Patient (home-user, OTC)

Clinician (Rx)

Keep it simple – Less is more

Test instructions on sample groups

Communication by symbols – ISO 15223

“Write It Right” – FDA guidance document
KISS
Post-Market Regulations

Complaints

Medical Device Reporting

Recalls
Complaints – CFR 820.198

“Any written, electronic, oral communication alleging deficiency related to
identity, quality, durability, reliability, safety, effectiveness, of device after
distribution into market”.

Healthcare workers must report to FDA and manufacturer
Medical Device Reporting Regulations
803.50

Mandatory reporting to FDA

Any healthcare treatment facility

Serious injury: life-threatening, permanent harm, requires medical intervention

HEAR IT, REPORT IT!
Types of Medical Device Reports

30 Day - device may cause serious injury or death

5 Day – device has caused serious injury or death, and remedial action
required to prevent unreasonable risk of substantial harm to public health

HEAR IT, REPORT IT!
MAUDE DATABASE

Manufacturer and User Facility Device Experience

FDA database for MDR

Excellent design tool

Query by year, manufacturer, product type, failure type etc.

MAUDE is FDA’s “eyes & ears”
Recall Classification

Class 1 – high probability of causing an immediate, significant, and
irreversible health problem or death.

Class 2 – No danger of death or serious injury. May cause reversible health
problem.

Class 3 - No likelihood of any health problems occurring. Violates an FDA
regulation.
Class 1 Recalls
2014
2015
2016
Mechanical/component failure
11
11
7
software
10
4
2
sterility/contamination
10
0
0
electrical safety issues
10
5
7
connector compatibility/connector failure
8
3
1
packaging/labeling/instructions-for-use
6
1
0
Medical Error Estimates - 2014

Cardiovascular deaths 787,0001

Cancer deaths 589,0002

Deaths by medical error 210,0003

Medical/diagnostic errors 410,0004

90,000 deaths in 19845
1- American Heart Association
2- American Cancer Association
3,4,5 – Institute of Medicine (medication, imaging, diagnostic)
Design Needs
antimicrobial catheters, implants
disposable and/or antimicrobial garments, hospital linens
endoscopes with single-use components, increased access for cleaning
fail/safe medication labels and storage compartments
increase clarity, reduce artifacts in imaging modalities
ergonomics and training

Less complex device designs

Increase training – entire health system

Manufacturers through clinicians

“To Err is Human; Building a Safer Health System”.1
1
– Institute of Medicine 1999
Radionuclide Brachytherapy Devices
“consists of an encapsulated radionuclide to be placed inside the body for the
purpose of delivering localized radiation”
CFR 892.5730
Class 2 device
510(k) substantial equivalence to a predicate
Applicable Standards

ANSI N43.6 Classification of Sealed Radioactive Systems

NIST Calibration Standards for Specific Radionuclide Source Encapsulation

ASTM F2503 Magnetic Resonance Safety

FDA Guidance 2014 Establishing Safety & Compatibility of Implantables in
MR Environments

IEC 60601 Electrical Safety Hospital Equipment and Medical Devices

ISO 10993 Biocompatibility
Radionuclide Data

Source of radioactive material

% contaminants

Half-life

Decay mode

Energy units
Radionuclide Output

Method used in measuring emitted energy

Dose-distribution curves

Disposal safety
Encapsulation Vessel

Material description/characteristics

Biocompatible according to ISO 10993 standards

Affect of vessel on photon spectrum; are dosimetry calculations affected

Certification from Nuclear Regulatory Commission allowing for interstate
shipment of radionuclide-device
TRAMF Probe

Safety and Compatibility IEC 60601

Compatible with other existing patient devices (implantable or external)
Sterilization

Does method affect performance of therapy?

Multiple use - decontamination methods
FDA Brachytherapy Guidance

“Guidance for Submission of Premarket Notifications for Photon Emitting
Brachytherapy Sources” August 2000
FDA Clinical Guidance

“Evaluation and Reporting of Age, Race, Ethnicity Data in Medical Device
Clinical Studies” June 2016
Will FDA ever approve my product?
Working With FDA

Stay engaged - Office of Device Evaluation

Sometimes you’re the “teacher” and FDA’s the “student”

And visa versa

Communicate with science, not emotion

Stay positive

PATIENCE is a VIRTUE!!!
Conclusion
Much success in all your future careers and endeavors! Any questions please
contact me at [email protected].