1) The document provides an overview of the FDA premarket review process for medical devices, with an emphasis on biocompatibility evaluation and regulations regarding device materials. 2) Key aspects of the premarket review process are outlined, including device classification and types of premarket submissions. Biocompatibility testing requirements are discussed, with tests selected based on the intended use and patient exposure to the device. 3) Recognized standards for materials and biocompatibility testing are reviewed, with the importance of evaluating the final device rather than raw materials emphasized. Useful online FDA resources are also presented.

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DESIGN OF IMPLANTABLE DEVICE –
UNDERSTANDING THE PREMARKET REVIEW
PROCESS AND “MATERIAL REGULATIONS”
FOR IMPLANTABLE MEDICAL DEVICE
Xin Fu, Ph.D., D.A.B.T.
Pharmacologist
FDA/CDRH/ODE/DRGUD/ULDB
September 19, 2012
San Diego, CA
2nd Annual Design of Implantable Device Conference

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Outline
Overview of premarket review process of
medical devices, with emphasis on
biocompatibility evaluation
Review of device materials

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Legal Definition of Device
Source - Federal Food, Drug, and Cosmetic Act, section 201 (h)
The term "device" (except when used in paragraph (n) of this
section and in sections 301(i), 403(f), 502(c), and 602(c))
means an instrument, apparatus, implement, machine,
contrivance, implant, in vitro reagent, or other similar or related
article, including any component, part, or accessory, which is
(1) recognized in the official National Formulary, or the United States
Pharmacopeia, or any supplement to them,
(2) 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
(3) intended to affect the structure or any function of the body of man or other
animals, and which does not achieve 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 its
primary intended purposes.

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Medical Device Regulation Overview
To determine whether the device is reasonably safe and
effective for the intended use
Law, Regulation, Policy, and Guidance
Law – passed by Congress and signed by the President
Regulation – developed by FDA to interpret and implement the
law
proposed in federal register (FR), receive comments, and then
finalized in FR
Policy – agency’s philosophical approach
Guidance – recommendations to sponsors and review staff on
agency’s policy interpretation for a regulatory issue
Review is based on the device classification

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Device Classification
Class I
Low risk, general controls are sufficient in most cases (misbranding,
adulteration, registration & listing, labeling, GMP, etc.)
Generally exempt from premarket review
Class II
General controls are insufficient, but there is sufficient information to
establish special controls (e.g. standard, guidance) to assure safety and
effectiveness
Premarket notification 510(k) is generally required
Class III
General / special controls are insufficient to assure safety and effectiveness
Premarket approval (PMA) is generally required
Need additional postmarketing requirements
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPCD/classification.cfm

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Type of Submissions
Premarket Approval (PMA)
Premarket Notification (510(k))
Investigational Device Exemptions (IDE)
Humanitarian Device Exemption (HDE)
Pre-Submissions (pre-Sub)
Evaluation of Automatic Class III Designation (de novo)
513(g) Request
Reclassification Petition

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New Developments
Establishes more frequent communication with
industry during the review process
Increased interactive review leading to fewer rounds of
deficiency/response prior to reaching an SE or NSE decision
Implements revised Refused to Accept (RTA) policy
to ensure better submission quality
Mandatory electronic copy (eCopy)
New performance goals with increased tracking,
monitoring, and reporting
Introduces a structured Pre-Submission program
Provides a new de novo pathway (not part of MDUFA III)

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Basic Content in Submissions
Intended use and Indication for use
Device description
Mode of action and mechanism
Safety and Effectiveness evaluation or
determination of substantial equivalence
Risk and benefit analysis
Labeling
Reasonably safe and effective
benefits > risks
provide clinically significant results

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Types of data
Preclinical
Material and chemical characterization (especially for in situ polymerizing
polymer, degradable material, nanoparticles and other novel materials)
Bench Performance Testing (e.g., mechanical, electrical, electromagnetic
interference, compatibility with accessories/auxiliaries, thermal safety,
optical, etc)
Biocompatibility
Animal Study
Sterility, packaging, shelf life/stability
Software validation
Clinical Study, when applicable
IDE – new guidance on pivotal study design from CDRH
Outside US (OUS) clinical study when shown to be applicable to the US
population
Well-documented case histories, reports of significant human experience
Postmarket information (if available) and literature

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Considerations in Preclinical Testing
Test on final (representative) device
Manufacturing, including sterilization, may affect biocompatibility of
final device
Test under the worst case scenario (e.g. aged vs. unaged, post
sterilization)
Test selection should be justified for intended use, material
characteristics and properties
Test method and pass/fail criteria should be justified
Use recognized standards
Provide rationale for study design and evaluation when recognized
standard is not used or not available
Justified numbers of representative samples should be
tested
Provide adequate test reports and/or properly completed
standard forms

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Biocompatibility
Biocompatibility
Property of a device or specific material used in the device, which
shows no toxicity or acceptable tolerance when used as it is
intended
State of a material in a physiological environment, without the
material adversely affecting the tissue, or the tissues adversely
affecting the material
Biocompatibility evaluation is biological evaluation of
medical devices to determine the toxicity potential resulting
from body contact with the device.
Factors affect biocompatibility
Chemical and physical properties of materials (e.g., leachables,
formulation, surface properties)
Host response
Intended use

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ISO 10993-1:2009, ASTM F748-06, and FDA Bluebook Memo
G95-1 provide general principles of tests and recommendation
of test selection.
FDA Bluebook Memo G95-1 provides general instructions for the
use of ISO 10993-1 standard.
There are slight differences in recommended tests between ISO
10993-1 and FDA Bluebook Memo G95-1.
G95-1 identifies additional tests for some device categories; A
major draft update to G95-1 is coming.
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/uc
m080735.htm
Testing selection is based on categorization of device and
matches the patient exposure to the device.
Nature of tissue/body contact
Contact duration
Implant Biocompatibility Evaluation

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Biocompatibility Tests for Implants
(FDA blue book memo G95-1)
To support premarket submission, studies conducted according to respective FDA recognized
standards and are in compliance with 21 CFR Part 58 GLP regulations are generally required.
In lieu of chronic toxicity/carcinogenicity testing of the device, proper toxicological risk
assessment based on adequate chemical characterization of the device is often sufficient and
acceptable.

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Test article
Final device, not raw material, should be tested with proper
controls.
If representative coupons are used instead of the final device,
additional comparative testing is often needed to compare the
surface properties and chemistry between the coupon and device
Animal study for further safety and function evaluation can be
common for certain implant devices, which provides additional
evaluations of target organ specific biocompatibility and
systemic toxicity.
For certain devices made of well characterized materials
(chemically and physically) that have long history of safe use,
some or all testing may not be necessary (e.g., certain alloys)
Implant Biocompatibility Evaluation

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Review of Device Materials
CDRH regulates medical devices, not materials
Material selection is critical in design and development of
medical devices
Mechanical and physical properties
Biocompatibility
Other considerations (e.g., sterilization, electromagnetic
compatibility and electrical safety, supply and cost)
Material supplier can submit material master file to FDA to
provide additional confidential material information
Manufacturing process can significantly affect the material
properties, so evaluation of raw material cannot replace evaluations
of the final device
Use of FDA recognized international and national standards
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm

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Search for recognized standard database, by standard organization, type of
standard, specific type of device (via panel, product code, regulation number),
specific category (e.g., biocompatibility, material, nanotechnology, software,
sterility, etc), standard reference number/title/key word etc.
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfStandards/search.cfm

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Use of Standards on Materials
98 FDA recognized standards on materials
74 ASTM standards and 24 ISO standards
Material specifications and standard test method
More material-related standards may be found under
each categories for specific clinical indication
Supplementary information sheet (SIS) for each
recognized standard specifies extent of recognition
Performance and biocompatibility evaluations of the
final device are often required even if the
conformance to a FDA recognized standard is
provided for the material used in the device

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Useful Online FDA Resources
Medical device database
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
Databases/default.htm
Medical device guidance
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
GuidanceDocuments/default.htm

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Medical Device Database

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Medical Device Guidance

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Successful Premarket Submission
Propose well defined intended use/indication for use
Provide clear and adequate device description and
characterization
Use good science, be current
Contribute to basic research, get involved in development of standard
methods to test novel materials and devices
Incorporate toxicological risk assessment in early
development of device and material selection
Conduct proper risk and benefit analysis
Have good understanding of premarket review process,
know when and where to seek help
Seek early and effective communication with regulatory
agency (pre-submissions)

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Thank you!