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

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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/ULDBSeptember 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 purposesthrough 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 GuidanceLaw – passed by Congress and signed by the PresidentRegulation – 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 approachGuidance – 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 ILow risk, general controls are sufficient in most cases (misbranding, adulteration, registration & listing, labeling, GMP, etc.)Generally exempt from premarket review

Class IIGeneral controls are insufficient, but there is sufficient information to establish special controls (e.g. standard, guidance) to assure safety and effectivenessPremarket notification 510(k) is generally required

Class IIIGeneral / special controls are insufficient to assure safety and effectivenessPremarket approval (PMA) is generally requiredNeed 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 qualityMandatory electronic copy (eCopy)New performance goals with increased tracking, monitoring, and reportingIntroduces a structured Pre-Submission programProvides a new de novo pathway (not part of MDUFA III)

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Basic Content in Submissions

Intended use and Indication for useDevice descriptionMode of action and mechanismSafety and Effectiveness evaluation or determination of substantial equivalence Risk and benefit analysisLabeling

Reasonably safe and effective benefits > risks

provide clinically significant results

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Types of data

PreclinicalMaterial 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 StudySterility, packaging, shelf life/stabilitySoftware validation

Clinical Study, when applicableIDE – new guidance on pivotal study design from CDRHOutside 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) deviceManufacturing, including sterilization, may affect biocompatibility of final deviceTest 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 justifiedUse recognized standardsProvide 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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BiocompatibilityBiocompatibility

Property of a device or specific material used in the device, which shows no toxicity or acceptable tolerance when used as it is intendedState 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 biocompatibilityChemical and physical properties of materials (e.g., leachables, formulation, surface properties)Host responseIntended 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/ucm080735.htm

Testing selection is based on categorization of device and matches the patient exposure to the device.

Nature of tissue/body contactContact 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 articleFinal 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 propertiesBiocompatibilityOther 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 standardshttp://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 Materials98 FDA recognized standards on materials

74 ASTM standards and 24 ISO standardsMaterial 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 databasehttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/

Databases/default.htm

Medical device guidancehttp://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 useProvide clear and adequate device description and characterizationUse 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 selectionConduct 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!