1
DESIGN OF IMPLANTABLE DEVICE –
UNDERSTANDING THE PREMARKET REVIEW
PROCESS AND “MATERIAL REGULATIONS”
FOR IMPLANTABLE MED...
2
Outline
Overview of premarket review process of
medical devices, with emphasis on
biocompatibility evaluation
Review of ...
3
Legal Definition of Device
Source - Federal Food, Drug, and Cosmetic Act, section 201 (h)
The term "device" (except when...
4
Medical Device Regulation Overview
To determine whether the device is reasonably safe and
effective for the intended use...
5
Device Classification
Class I
Low risk, general controls are sufficient in most cases (misbranding,
adulteration, regist...
6
Type of Submissions
Premarket Approval (PMA)
Premarket Notification (510(k))
Investigational Device Exemptions (IDE)
Hum...
7
New Developments
Establishes more frequent communication with
industry during the review process
Increased interactive r...
8
Basic Content in Submissions
Intended use and Indication for use
Device description
Mode of action and mechanism
Safety ...
9
Types of data
Preclinical
Material and chemical characterization (especially for in situ polymerizing
polymer, degradabl...
10
Considerations in Preclinical Testing
Test on final (representative) device
Manufacturing, including sterilization, may...
11
Biocompatibility
Biocompatibility
Property of a device or specific material used in the device, which
shows no toxicity...
12
ISO 10993-1:2009, ASTM F748-06, and FDA Bluebook Memo
G95-1 provide general principles of tests and recommendation
of t...
13
14
Biocompatibility Tests for Implants
(FDA blue book memo G95-1)
To support premarket submission, studies conducted accor...
15
Test article
Final device, not raw material, should be tested with proper
controls.
If representative coupons are used ...
16
Review of Device Materials
CDRH regulates medical devices, not materials
Material selection is critical in design and d...
17
Search for recognized standard database, by standard organization, type of
standard, specific type of device (via panel...
18
Use of Standards on Materials
98 FDA recognized standards on materials
74 ASTM standards and 24 ISO standards
Material ...
19
20
Useful Online FDA Resources
Medical device database
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/
Data...
21
Medical Device Database
22
Medical Device Guidance
23
Successful Premarket Submission
Propose well defined intended use/indication for use
Provide clear and adequate device ...
24
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DESIGN OF IMPLANTABLE DEVICE – UNDERSTANDING THE PREMARKET REVIEW PROCESS AND “MATERIAL REGULATIONS” FOR IMPLANTABLE MEDICAL DEVICE

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Xin Fu, Ph.D., D.A.B.T.
Pharmacologist
FDA/CDRH/ODE/DRGUD/ULDB

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

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DESIGN OF IMPLANTABLE DEVICE – UNDERSTANDING THE PREMARKET REVIEW PROCESS AND “MATERIAL REGULATIONS” FOR IMPLANTABLE MEDICAL DEVICE

  1. 1. 1 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
  2. 2. 2 Outline Overview of premarket review process of medical devices, with emphasis on biocompatibility evaluation Review of device materials
  3. 3. 3 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.
  4. 4. 4 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
  5. 5. 5 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
  6. 6. 6 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
  7. 7. 7 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)
  8. 8. 8 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
  9. 9. 9 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
  10. 10. 10 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
  11. 11. 11 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
  12. 12. 12 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
  13. 13. 13
  14. 14. 14 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.
  15. 15. 15 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
  16. 16. 16 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
  17. 17. 17 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
  18. 18. 18 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
  19. 19. 19
  20. 20. 20 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
  21. 21. 21 Medical Device Database
  22. 22. 22 Medical Device Guidance
  23. 23. 23 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)
  24. 24. 24 Thank you!

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