FDA Guidance for Heart Valve Replacement

Draft Guidance for Industry and FDA

Staff !

Heart Valves - Investigational Device

Exemption (IDE) and Premarket

Approval (PMA) Applications

DRAFT GUIDANCE !

This guidance document is being distributed for comment purposes only.!!

Document issued on: January 20, 2010

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U.S. Department of Health and Human Services

Food and Drug Administration

Center for Devices and Radiological Health

Circulatory Support and Prosthetic Devices Branch

Division of Cardiovascular Devices

Office of Device Evaluation

http://www.fda.gov/dockets/ecomments

Contains Nonbinding Recommendations !

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Preface

Additional Copies!

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http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/umc193096.htm

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/umc193096.htm

mailto:[email protected]


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Table of Contents

I.! INTRODUCTION.........................................................................................................................................1!

II.! BACKGROUND............................................................................................................................................2!

III.! SCOPE ...........................................................................................................................................................2!

IV.! RISK ANALYSIS..........................................................................................................................................3!

V.! THE PRE-SUBMISSION PROCESS..........................................................................................................4!

VI.! IDE AND PMA APPLICATIONS: GENERAL CONSIDERATIONS...................................................4!

VII.! TERMS AND DEFINITIONS......................................................................................................................5!

VIII.! DEVICE DESCRIPTION.............................................................................................................................5!

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IX.! PYROGENICITY .........................................................................................................................................8!

X.! STERILIZATION.........................................................................................................................................8!

XI.! PRECLINICAL IN VITRO ASSESSMENT .............................................................................................10!

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XII.! PRECLINICAL ANIMAL STUDIES .......................................................................................................14!

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XIII.! CLINICAL INVESTIGATIONS ...............................................................................................................18!

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XIV.! PMA SUPPLEMENTS ...............................................................................................................................25!

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XV.! PROFESSIONAL LABELING..................................................................................................................26!

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XVI.! PATIENT LABELING...............................................................................................................................27!

APPENDIX A. SHELF LIFE VALIDATION........................................................................................................28!

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APPENDIX B. CAVITATION TESTING FOR RIGID HEART VALVES.......................................................32!

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APPENDIX C. BERNOULLI VERIFICATION...................................................................................................34!

APPENDIX D. ECHOCARDIOGRAPHY PROTOCOL.....................................................................................35!

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Draft Guidance for Industry and FDA Staff !

Heart Valves - Investigational Device Exemption

(IDE) and Premarket Approval (PMA)

Applications !

This draft guidance, when finalized, will represent the Food and Drug Administration's

(FDA's) current thinking on this topic. It does not create or confer any rights for or on any

person and does not operate to bind FDA or the public. You can use an alternative approach

if the approach satisfies the requirements of the applicable statutes and regulations. If you

want to discuss an alternative approach, contact the FDA staff responsible for implementing

this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number

listed on the title page of this guidance.

I. Introduction !

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3-#2#,-1!9)29%(!?%:,:G!8#.1-&%!9)29%(FG!#.!9)29%(!1#&('.+1'%*!#0!)!1#$3-&)'-#&!#0!8.#('/%'-1!)&*!

3-#2#,-1!$)'%.-)2(:!!!

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Classification

(21 CFR)

Class Product

Code

Description

MT6:D5LE! UUU! <WS! J%82)1%$%&'!/%).'!9)29%!

†! UUU! Icd! @%).'!9)29%G!$%1/)&-1)2!

† UUU! IcJ! @%).'!9)29%G!&#&C)22#,.)0'!'-((+%!

†J%P+-.%(!8.%$).=%'!)88.#9)2!)882-1)'-#&!3%0#.%!$).=%'-&,!?(%%!(%1'-#&!EKD?)F!#0!'/%!A%*%.)2!

A##*G!<.+,G!)&*!"#($%'-1!B1'!?LK!`:;:":!DH61?)FFF:!

!

\/%!.%1#$$%&*)'-#&(!-&!'/-(!*#1+$%&'!$)7!)2(#!)8827!'#!&%4!'78%(!#0!/%).'!9)29%(!?%:,:G!'-((+%C

%&,-&%%.%*!9)29%(G!8#27$%.!2%)02%'!9)29%(F:!!!

!

\/-(!,+-*)&1%!)2(#!)882-%(!'#!8%.1+')&%#+(27!*%2-9%.%*!9)29%(k!/#4%9%.G!*-00%.%&'!#.!)**-'-#&)2!*5'

6*,$19'*5'6*61'8.%12-&-1)2G!)&*!12-&-1)2!('+*-%(!$)7!3%!)88.#8.-)'%!0#.!(+1/!*%9-1%(G!*%8%&*-&,!#&!

'/%!(8%1-0-1!*%9-1%!*%(-,&G!'/%!8.#8#(%*!-&*-1)'-#&(!0#.!+(%G!)&*!'/%!.%(+2'(!#0!7#+.!.-(=!)&)27(-(:Z!!

c%!.%1#$$%&*!7#+!1#&')1'!'/%!"-.1+2)'#.7!)&*![.#('/%'-1(!<%9-1%(!_.)&1/!'#!*-(1+((!82)&&%*!

(+3$-((-#&(!0#.!8%.1+')&%#+(27!*%2-9%.%*!9)29%(:!

!

\/-(!,+-*)&1%!*#%(!&#'!)8827!'#!9)29%C.%8)-.!*%9-1%(!?%:,:G!)&&+2#82)('7!.-&,(!?8.#*+1'!1#*%!

]J@G!MT6:DM66FE!#.!$-'.)2!9)29%!.%8)-.!*%9-1%(!?8.#*+1'!1#*%!^]>FF:!!

!

\/-(!,+-*)&1%!*#%(!&#'!)8827!'#!)22#,.)0'!/%).'!9)29%(:!![2%)(%!1#&')1'!A<Bf(!"%&'%.!0#.!

_-#2#,-1(G!S9)2+)'-#&!)&*!J%(%).1/!?"_SJF!0#.!-&0#.$)'-#&!)3#+'!'/%!.%,+2)'#.7!.%P+-.%$%&'(!

0#.!)22#,.)0'!/%).'!9)29%(:H!!!

!

\/-(!,+-*)&1%!*#%(!&#'!)8827!'#!$#.%!'/)&!$-&-$)227!$)&-8+2)'%*!)22#,.)0'!/%).'!9)29%(!?8.#*+1'!

1#*%!R@BFG!4/-1/!.%P+-.%!12%).)&1%!#0!)!EK6?=F!8.-#.!'#!$).=%'-&,:!!!

!

IV. Risk Analysis

J-(=!)&)27(-(!-(!)!0#.$)2!8.#1%*+.%!37!4/-1/!7#+!%('-$)'%!'/%!8.#3)3-2-'7!)&*!*%,.%%!#0!/).$!)!

*%9-1%!.%8.%(%&'(G!)&*!82)&!)88.#8.-)'%!-&9%('-,)'-#&(!)11#.*-&,27!'#!$-'-,)'%!'/#(%!.-(=(!'#!'/%!

%Y'%&'!8#((-32%:!!c%!.%1#$$%&*!'/)'!7#+!8%.0#.$!)!.-(=!)&)27(-(!)(!*%(1.-3%*!-&!U;R!EMZ6NL66E!

#.!-'(!%P+-9)2%&'!?%:,:G!/)g).*!-*%&'-0-1)'-#&G!)((#1-)'%*!0)-2+.%!$#*%(G!.-(=!%('-$)'-#&G!.-(=!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Z!A#.!.%1#$$%&*)'-#&(!'/)'!$)7!3%!)882-1)32%!'#!('+*-%(!#0!*%2-9%.7!(7('%$(!0#.!8%.1+')&%#+(27!

*%2-9%.%*!9)29%(G!(%%!'/%!(%1'-#&(!.%2)'%*!'#!*%2-9%.7!(7('%$!'%('-&,!*%(1.-3%*!-&!'/%!A<B!

,+-*)&1%G!Non-Clinical Tests and Recommended Labeling for Intravascular Stents and

Associated Delivery Systems!)'!

/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$6

TKMHD:/'$:! !E!;%%!'/%!A<B!,+-*)&1%G!Guidance for Annuloplasty Rings 510(k) Submissions!)'!

/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$6

TDHZZ:/'$:! !H!;%%!/''8NOO444:0*):,#9O13%.O'-((:/'$:!

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http://www.fda.gov/cber/tiss.htm




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%9)2+)'-#&G!.-(=!1#&'.#2G!)&*!.-(=!.%9-%4F:!!W#+.!U<S!)882-1)'-#&(!(/#+2*!-&12+*%!7#+.!-&-'-)2!.-(=!

)&)27(-(!0#.!7#+.!*%9-1%!)&*!7#+.![>B!(/#+2*!-&12+*%!)&!+8*)'%*!.-(=!)&)27(-(:!!!

V. The Pre-Submission Process

\#!+(%!'/-(!,+-*)&1%!%00%1'-9%27G!4%!%&1#+.),%!7#+!'#!/)9%!0.%P+%&'!)&*!%).27!-&'%.)1'-#&!4-'/!

A<B!.%9-%4%.(:!!c%!)2(#!%&1#+.),%!7#+!'#!+(%!A<Bj(!8.%C(+3$-((-#&!8.#1%*+.%!0#.!'/-(!

-&'%.)1'-#&:!!\/%!8+.8#(%!#0!)!8.%C(+3$-((-#&!-&'%.)1'-#&!-(!'#!8.#9-*%!)!$%1/)&-($!0#.!7#+!)&*!

A<B!'#!1#$$+&-1)'%!-&0#.$)227!)3#+'!8.%12-&-1)2!('+*-%(!?-:%:G!3%&1/!)&*O#.!)&-$)2F!3%0#.%!7#+!

1#&*+1'!'/%(%!('+*-%(G!#.!)3#+'!)!12-&-1)2!8.#'#1#2!3%0#.%!7#+!(+3$-'!)&!U<S!)882-1)'-#&:!!W#+.!

8.%C(+3$-((-#&!(/#+2*!-&12+*%!)!*%(1.-8'-#&!#0!'/%!*%9-1%G!-'(!-&'%&*%*!+(%G!)&*!)!.-(=!)&)27(-(:!!

W#+.!8.%C(+3$-((-#&!(/#+2*!)2(#!-&12+*%!(+$$).-%(!#0!7#+.!8.#8#(%*!'%('!82)&G!8.#'#1#2(G!)&*!

-&9%('-,)'-#&)2!82)&(:!!U&!)**-'-#&G!7#+.!8.%C(+3$-((-#&!(/#+2*!1#&')-&!12%).27!*%0-&%*!P+%('-#&(!

0#.!*-(1+((-#&!4-'/!A<B:!!W#+!(/#+2*!-&12+*%!8-1'+.%(G!(2-*%(G!9-*%#(G!#.!()$82%(G!-0!7#+!3%2-%9%!

'/%7!).%!+(%0+2!'#!+&*%.(')&*!7#+.!*%9-1%:!

!

VI. IDE and PMA Applications: General Considerations

"2-&-1)2!('+*-%(!1#&*+1'%*!-&!'/%!`&-'%*!;')'%(!-&!(+88#.'!#0!)![>B!)88.#9)2!$+('!3%!1#&*+1'%*!

+&*%.!'/%!U&9%('-,)'-#&)2!<%9-1%!SY%$8'-#&(!?U<SF!.%,+2)'-#&G!LK!"AJ![).'!MKL:!!A<B!3%2-%9%(!

*%9-1%(!)**.%((%*!37!'/-(!,+-*)&1%!*#1+$%&'!).%!(-,&-0-1)&'!.-(=!*%9-1%(!)(!*%0-&%*!-&!LK!"AJ!

MKL:D?$F:T!!U&!)**-'-#&!'#!'/%!.%P+-.%$%&'!#0!/)9-&,!)!A<BC)88.#9%*!U<SG!(8#&(#.(!$+('!

1#$827!4-'/!'/%!.%,+2)'-#&(!,#9%.&-&,!-&('-'+'-#&)2!.%9-%4!3#).*(!?LK!"AJ![).'!EHF!)&*!

-&0#.$%*!1#&(%&'!?LK!"AJ![).'!E6F:!

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-&12+*-&,!)22!8.-#.!12-&-1)2G!)&-$)2!)&*!2)3#.)'#.7!'%('-&,!?LK!"AJ!MKL:L6!?3F?LF!)&*!MKL:LT?)FF:!!

B!1#$82%'%!.%8#.'!4#+2*!-&12+*%!*5'6*,$1!2)3#.)'#.7!'%('-&,!.%(+2'(G!*5'6*61!)&-$)2!('+*7!'%('-&,!

.%(+2'(G!)&*!'/%!8.#'#1#2(!0#.!'/%!12-&-1)2!-&9%('-,)'-#&(!0#.!8.-#.!-&9%('-,)'-#&(:!!

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3%0#.%!7#+!(+3$-'!7#+.!U<S:!!U'!$)7!3%!)88.#8.-)'%G!/#4%9%.G!'#!1#$82%'%!1%.')-&!2#&,C'%.$!*5'

6*,$1!'%('(!4/-2%!7#+!1#&*+1'!7#+.!12-&-1)2!('+*7:!!W#+!(/#+2*!*-(1+((!7#+.!.)'-#&)2%!0#.!

(+3$-((-#&!#0!)&7!'%('(!0#.!4/-1/!'%('-&,!-(!&#'!1#$82%'%!4-'/!'/%!.%9-%4!3.)&1/!3%0#.%!

(+3$-''-&,!7#+.!U<S:!!c%!3%2-%9%!'/)'!-&!)22!1)(%(!7#+!(/#+2*!1#$82%'%!7#+.!)11%2%.)'%*!4%).!

'%('-&,!3%0#.%!7#+!(+3$-'!7#+.!U<S:!!!

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)88.#9%!#.!*%&7!)88.#9)2!#0!'/%!)882-1)'-#&G!-&12+*-&,!'/%!$%'/#*(!)&*!8.#'#1#2(!+(%*!-&!12-&-1)2!

-&9%('-,)'-#&(!-&9#29-&,!/+$)&!(+3l%1'(!?LK!"AJ!MKZ:L6?3F?HFF:!!W#+!$+('!8.#9-*%!'/%!.%(+2'(!

0.#$!)22!8.%12-&-1)2!*5'6*,$1G!8.%12-&-1)2!*5'6*61G!)&*!12-&-1)2!'%('-&,!7#+!/)9%!1#&*+1'%*:!!U*:!!

!

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!T!;%%!/''8NOO444:0*):,#9O#1O#/.'O-.3(O*%9-1%(:/'$2m.-(=:!

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VII. Terms and Definitions

c%!.%1#$$%&*!'/)'!7#+!+(%!'/%!'%.$(!)&*!*%0-&-'-#&(!*%0-&%*!-&!U;R!EMZ6NL66E!4/%&!8.%8).-&,!

U<S(!)&*![>B(!0#.!.%82)1%$%&'!/%).'!9)29%(:!!U&!)**-'-#&G!A<B!+(%(!'/%!0#22#4-&,!'%.$(N!!!

!

Replacement Heart Valve:!!B2'/#+,/!U;R!EMZ6NL66E!+(%(!'/%!'%.$!h/%).'!9)29%!(+3('-'+'%i!

'#!$%)&!)!8.#('/%'-1!/%).'!9)29%G!4%!+(%!'/%!'%.$!h.%82)1%$%&'!/%).'!9)29%i!-&!LK!"AJ!

MT6:D5LE!)&*!-&!'/-(!,+-*)&1%:!!c%!+&*%.(')&*!'/%!'%.$!h.%82)1%$%&'!/%).'!9)29%i!'#!3%!

%P+-9)2%&'!'#!h/%).'!9)29%!(+3('-'+'%i!?+(%*!-&!U;R!EMZ6NL66EF!)&*!%P+-9)2%&'!'#!(+1/!'%.$(!

)(!h8.#('/%'-1!/%).'!9)29%i!)&*!h/%).'!9)29%!-$82)&'i!0#.!8+.8#(%(!#0!'/-(!,+-*)&1%:!

!

Pressure Gradient:!!B2'/#+,/!U;R!EMZ6NL66E!+(%(!'/%!'%.$(!h$%)&!8.%((+.%!*-00%.%&1%i!

)&*!h8%)=!8.%((+.%!*-00%.%&1%Gi!4%!+(%!'/%!'%.$!h$%)&!8.%((+.%!,.)*-%&'i!-&!'/-(!,+-*)&1%!

-&('%)*!#0!h$%)&!8.%((+.%!*-00%.%&1%i!)&*!'/%!'%.$!h8%)=!8.%((+.%!,.)*-%&'i!-&!'/-(!,+-*)&1%!

-&('%)*!#0!h8%)=!8.%((+.%!*-00%.%&1%i!3%1)+(%!'/%!'%.$!h8.%((+.%!,.)*-%&'i!-(!+(%*!)2$#('!

%Y12+(-9%27!-&!'/%!`:;:!12-&-1)2!).%&)!)&*!-&!'/%!4#.2*4-*%!12-&-1)2!/%).'!9)29%!2-'%.)'+.%:!!c%!

.%1#,&-g%!'/)'!'/%!'%.$!h8.%((+.%!,.)*-%&'i!/)(!)!9%.7!(8%1-0-1!*%0-&-'-#&!-&!%&,-&%%.-&,!?-:%:G!

8.%((+.%O*-(')&1%F!'/)'!-(!&#'!1#&(-('%&'!4-'/!'/%!+(%!#0!'/-(!'%.$!-&!'/-(!,+-*)&1%:!

!

Tissue Annulus Diameter:!!\/%!'-((+%!)&&+2+(!*-)$%'%.!?\B<F!-(!*%0-&%*!-&!U;R!EMZ6NL66E!

)(!'/%!*-)$%'%.!-&!$-22-$%'%.(!)'!'/%!($)22%('!02#4!).%)!4-'/-&!'/%!8)'-%&'f(!9)29%!)&&+2+(:!!

\/%!9)29%!(-g%!-(!&#4!*-('-&1'27!1#..%2)'%*!4-'/!'/%!\B<!)'!-'(!&)..#4%('!#8%&-&,:!!B(!(+1/G!

7#+.!*%(-,&)'-#&!#0!)!.%82)1%$%&'!/%).'!9)29%!(/#+2*!-&*-1)'%!'/%!\B<!#0!'/%!.%1-8-%&'!-&!

$-22-$%'%.(!?-:%:G!\B<!-(!&#4!.%0%..%*!'#!)(!'/%!*%(-,&)'%*!9)29%!(-g%F:!!c%!.%1#$$%&*!'/)'!

7#+!0#22#4!'/-(!(')&*).*-g%*!*%0-&-'-#&!'#!)((+.%!'/%!1#..%1'!(-g%*!9)29%!-(!+(%*:!

!

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EMZ6NL66EG!4%!.%1#$$%&*!'/)'!7#+!-&12+*%!'/-(!-&0#.$)'-#&!-&!7#+.!)882-1)'-#&:!!!

VIII. Device Description

U&!7#+.!U<S!)&*![>B!)882-1)'-#&!7#+!$+('!-&12+*%!)!*%(1.-8'-#&!#0!'/%!*%9-1%!?LK!"AJ!

MKL:LE?*F!)&*!LK!"AJ!MKZ:L6?3F?DF?--FF:!!c%!.%1#$$%&*!'/)'!7#+!8.#9-*%!'/%!0#22#4-&,!

*%(1.-8'-9%!-&0#.$)'-#&!-&!7#+.!.%82)1%$%&'!/%).'!9)29%!U<S!#.![>B!)882-1)'-#&:!!!!

!

Device Parameters

W#+.!U<S!)&*![>B!)882-1)'-#&!(/#+2*!-&12+*%!)!*%(1.-8'-#&!#0!%)1/!#0!'/%!,%&%.)2!*%9-1%!

*%(-,&!8).)$%'%.(!2-('%*!3%2#4:!!B!')3+2).!0#.$)'!-(!*%(-.)32%G!(/#4&!-&!'/%!%Y)$82%!

0#22#4-&,!'/%!2-('!3%2#4:!

! U$82)&')'-#&G!-&12+*-&,!9)29%!2#1)'-#&(G!)&&+2+(!8#(-'-#&(G!)&*!(+'+.%!'%1/&-P+%!

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9)29%(G!'/%!0+227!#8%&%*!)&,2%G!0+227!12#(%*!)&,2%G!)&*!'.)9%2!).1!0.#$!#8%&%*!'#!

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! @#+(-&,O;'%&'G!*%(1.-3-&,!'/%!2%)02%'!).'-1+2)'-#&!$%1/)&-($!)&*!('%&'!$)'%.-)2!

! ;%4-&,!1+00G!-&*-1)'-&,!4/%'/%.!'/%!(%4-&,!1+00!-(!.#')')32%!)&*!*%(1.-3-&,!'/%!

)'')1/$%&'!$%1/)&-($!)&*!$)'%.-)2!

! "#)'-&,(!)&*!'.%)'$%&'(G!-0!)&7G!%Y82)-&-&,!'/%!8+.8#(%!?%:,:G!!)&'-3-#'-1G!

)&'-'/.#$3#'-1G!)&'-1)21-0-1F!)&*!2#1)'-#&!

! B11%((#.-%(G!(+1/!)(!-$82)&')'-#&!'##2(!?%:,:G!/#2*%.G!.#')'#.G!2%)02%'!8.#3%G!(-g%.F:!

!

Valve General Design Parameters Tabular Format Example!GENERAL DESIGN FEATURES

PARAMETER DESCRIPTION

Valve locations(s):

Annulus position(s):

Implantation:

Suture technique:

No. leaflets/occluders:

Fully opened angle*:

Fully closed angle*:

Travel arc from opened to closed*:

Leaflets/ Occluder:

Material:

Radiopaque material: Radiopacity:

Location of radiopaque material:

Leaflet articulation mechanism: Housing/ Stent:

Material:

Rotatable/not:

Attachment mechanism:

Sewing cuff:

Material:

Purpose:

(antibiotic, antithrombotic, anticalcific, etc.)

Coatings/ Treatments:

Location:

Accessories: Implantation tools (holder, rotator, leaflet probe, sizer).

Other:

*Applicable only to rigid replacement heart valves.

!

W#+.!U<S!)&*![>B!)882-1)'-#&!(/#+2*!)2(#!-&12+*%!)!*%(1.-8'-#&!#0!%)1/!#0!'/%!*-$%&(-#&)2!

*%(-,&!8).)$%'%.(!2-('%*!3%2#4!0#.!%)1/!(-g%!7#+!82)&!'#!$).=%':!!!

! \-((+%!B&&+2+(!<-)$%'%.!?\B<F!?$$F!

! Q)29%!R+'%.!<-)$%'%.!?R<F!?*-1')'%*!37!1+00!R<F!?$$F! !

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! [.#0-2%!@%-,/'?(F!?$$F:! !

!

Packaging Information

W#+.!U<S!)&*![>B!)882-1)'-#&!$+('!-&12+*%!)!*%(1.-8'-#&!#0!'/%!8)1=-&,!$%'/#*(!+(%*!?LK!

"AJ!MKL:L6?3F?DF!)&*!LK!"AJ!MKZ:L6?3F?ZF?9FF:!!!c%!.%1#$$%&*!7#+!-&12+*%!8)1=),-&,!

*%(-,&!)&*!8%.0#.$)&1%!-&0#.$)'-#&!)(!*%(1.-3%*!3%2#4:!!B!')3+2).!0#.$)'!-(!*%(-.)32%G!)(!

(/#4&!-&!'/%!%Y)$82%!)'!'/%!%&*!#0!'/-(!(%1'-#&:!

!

1. Package Design!!

c%!.%1#$$%&*!'/)'!7#+!*%(1.-3%!'/%!8)1=),%!*%(-,&!)&*!-&12+*%!$)((!)&*!9#2+$%!?0#.!

8+.8#(%(!#0!1)21+2)'-&,!2#)*!*%&(-'7!0#.!('%.-2-g)'-#&!9)2-*)'-#&FG!)22!1#$8#&%&'(G!)&*!)&7!

0%)'+.%!'/)'!-&*-1)'%(!4/%'/%.!'/%!8)1=),%!/)(!3%%&!#8%&%*:!!W#+.!*%(1.-8'-#&!(/#+2*!

-&12+*%!(%)2-&,!8).)$%'%.(G!(+1/!)(!'-$%G!'%$8%.)'+.%G!)&*!2-*!12#(+.%!'#.P+%:!!W#+.!

*%(1.-8'-#&!(/#+2*!)2(#!-&12+*%!8%.0#.$)&1%!(8%1-0-1)'-#&(!0#.!'/%!('%.-2-g)'-#&!1712%(G!2-*G!

(%)2G!9)1++$!2%)=!.%(-(')&1%G!)&*!)&7!(%)2-&,!')8%!#.!'%$8%.)'+.%!-&*-1)'#.(:!!!

!

2. Temperature Sensor

A#.!9)29%(!'/)'!1#&')-&!3-#2#,-1)2!'-((+%G!(+1/!)(!8#.1-&%G!3#9-&%G!#.!%P+-&%!9)29%(G!4%!

.%1#$$%&*!'/)'!7#+!+(%!)!'%$8%.)'+.%!(%&(#.:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!-&12+*%!

-&0#.$)'-#&!)3#+'!/#4!7#+!9)2-*)'%!'/%!(%&(-'-9-'7!#0!'/%!(%&(#.:!

!

3. Storage for Valves that Contain Biological Tissue

c%!.%1#$$%&*!'/)'!7#+!8.#9-*%!)!2-('!#0!'/%!1#$8#&%&'(!#0!'/%!('#.),%!(#2+'-#&:!!c%!

)2(#!.%1#$$%&*!'/)'!7#+!-&*-1)'%!'/%!)$#+&'!#0!'/%!.%(-*+)2!('#.),%!(#2+'-#&!2%0'!#&!'/%!

9)29%!'-((+%!)&*!-&!'/%!+(%*!.-&(%!(#2+'-#&!)0'%.!'/%!9)29%!/)(!3%%&!.-&(%*!)11#.*-&,!'#!'/%!

8.#1%*+.%!(8%1-0-%*!-&!7#+.!2)3%2-&,:!!!

Package Information – Tabular Format Example

Package Information

Package mass and volume

for purposes of calculating load density for sterilization validation

Package components i.e., container (jar), holder, lid and seal components (sealing tape), components or feature that indicates if the package has been opened

Storage solution amount of the residual storage solution left on the valve tissue and in the used rinse solution after the valve has been rinsed according to the procedure specified in your labeling

PARAMETER SPECIFICATION (average, min)

Seal time, temperature, and pressure

Sealing parameters

Lid closure torque

! T


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!Maximum no. of sterilization cycles

Tensile strength Sealing tape

Shrinkage

Minimum seal width

Peel force

Seal

Burst strength

Lid removal torque

Vacuum leak resistance

Composition Storage solution

pH

Performance specifications

Temperature indicators

IX. Pyrogenicity

W#+!$+('!%(')32-(/!)&*!$)-&')-&!8.#1%*+.%(!0#.!)11%8')&1%!)1'-9-'-%(!?LK!"AJ!ML6:M6F:!!W#+!

$+('!%(')32-(/!)&*!$)-&')-&!8.#1%*+.%(!0#.!0-&-(/%*!*%9-1%!)11%8')&1%!'#!%&(+.%!'/)'!%)1/!

8.#*+1'-#&!.+&G!2#'G!#.!3)'1/!#0!0-&-(/%*!*%9-1%(!$%%'(!)11%8')&1%!1.-'%.-)!?LK!"AJ!ML6:M6?*FF:!!

B!.%82)1%$%&'!/%).'!9)29%!-(!)&!-$82)&'%*!*%9-1%k!'/%.%0#.%!4%!.%1#$$%&*!'/)'!7#+!'%('!7#+.!

*%9-1%!0#.!87.#,%&-1-'7!?(8%1-0-1)227!0#.!%&*#'#Y-&(F:!!c%!.%1#$$%&*!'/)'!7#+!8.#9-*%N!

! *%(1.-8'-#&!#0!'/%!$%'/#*!+(%*!'#!$)=%!'/%!*%'%.$-&)'-#&G!%:,:G!I-$+2+(!)$%3#17'%!27()'%!?IBIF!

! -*%&'-0-1)'-#&!#0!'/%!'%('-&,!%&*8#-&'!.%)1/%*!)&*!.)'-#&)2%!0#.!(%2%1'-&,!'/)'!%&*8#-&'!

! *%(1.-8'-#&!#0!'/%!%Y'.)1'-#&!'%1/&-P+%!+(%*!'#!#3')-&!'/%!'%('!02+-*!0.#$!'/%!'%('!*%9-1%G!(/#4-&,!'/)'!)22!12-&-1)227!.%2%9)&'!1#&')1'!(+.0)1%(!#0!'/%!'%('!*%9-1%!4%.%!

)((%((%*!

! -*%&'-0-1)'-#&!#0!'/%!.%0%.%&1%!$%'/#*!+(%*G!%:,:G!`&-'%*!;')'%(![/).$)1#8%-)!?`;[FG!B^;UOBB>U!;\!TLNL66LG!_)1'%.-)2!%&*#'#Y-&(!C!\%('!$%'/#*#2#,-%(G!

.#+'-&%!$#&-'#.-&,G!)&*!)2'%.&)'-9%(!'#!3)'1/!'%('-&,!#.!A<B!,+-*)&1%:!

X. Sterilization

c%!.%1#$$%&*!'/)'!7#+!0#22#4!'/%!('%.-2-g)'-#&!$%'/#*(!*%(1.-3%*!-&!U;R!EMZ6NL66EG!#.!

%P+-9)2%&'!$%)(+.%(:!

!

1. Non-Sterile Devices

U0!7#+!-&'%&*!'#!(+8827!7#+.!*%9-1%!&#&C('%.-2%G!4%!.%1#$$%&*!'/)'!7#+!%Y82)-&!7#+.!

.)'-#&)2%:!!W#+!(/#+2*!-&*-1)'%!8.#$-&%&'27!#&!7#+.!2)3%2-&,!'/)'!'/%!*%9-1%!-(!(+882-%*!

&#&C('%.-2%!)&*!8.#9-*%!-&('.+1'-#&(!0#.!)11%8')32%!+(%!8).)$%'%.(G!(+1/!)(!'%$8%.)'+.%G!

8.%((+.%G!*4%22!'-$%(!0#.!'/%!-&-'-)2!('%.-2-g)'-#&:!!B**-'-#&)227G!7#+!(/#+2*!-&12+*%!-&!7#+.!

! M


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

2)3%2-&,!4/%'/%.!.%C('%.-2-g)'-#&G!+(-&,!'/%(%!8).)$%'%.(G!-(!)88.#8.-)'%:!!\/%!

*%'%.$-&)'-#&!4/%'/%.!.%C('%.-2-g)'-#&!-(!)88.#8.-)'%!(/#+2*!3%!3)(%*!#&!'/%!9)2-*)'-#&!

'%('-&,!0#.!'/%!(')'%*!8).)$%'%.(G!)&*!'/%!&+$3%.!#0!.%('%.-2-g)'-#&(:!!

2. Resterilization

W#+.!2)3%2-&,!(/#+2*!8.#9-*%!-&('.+1'-#&(!0#.!)11%8')32%!8).)$%'%.(!'#!3%!+(%*G!(+1/!)(!

'%$8%.)'+.%G!8.%((+.%G!*4%22!'-$%(G!3)(%*!#&!9)2-*)'-#&(!*#&%!'#!9)2-*)'%!'/%(%!8).)$%'%.(!

)&*!&+$3%.(!#0!.%('%.-2-g)'-#&(:!!U0!7#+.!2)3%2-&,!-&*-1)'%(!7#+.!*%9-1%!-(!.%('%.-2-g)32%!

?-:%:G!0#.!8)1=),%(!'/)'!).%!h#8%&!3+'!+&+(%*iFG!4%!.%1#$$%&*!'/)'!7#+.!)882-1)'-#&!

-&12+*%N!

! )!.)'-#&)2%!(+88#.'-&,!'/%!()0%!)&*!%00%1'-9%!8%.0#.$)&1%!#0!7#+.!*%9-1%!)0'%.!.%('%.-2-g)'-#&!

! )!*%(1.-8'-#&!'/)'!*-00%.%&'-)'%(!3%'4%%&!('%.-2-g)'-#&!1#&*+1'%*!)'!'/%!$)&+0)1'+.-&,!0)1-2-'7!)&*!('%.-2-g)'-#&!8%.0#.$%*!37!/#(8-')2!(')00!

! 9)2-*)'-#&!#0!'/%!%00%1'!#0!.%('%.-2-g)'-#&!#&!'/%!9)29%:!!?Q)2-*)'-#&!(/#+2*!*%$#&('.)'%!'/)'!'/%!$)Y-$+$!&+$3%.!#0!.%('%.-2-g)'-#&(!.%1#$$%&*%*!-&!7#+.!

2)3%2-&,!*#%(!&#'!)00%1'!'/%!()0%!)&*!%00%1'-9%!8%.0#.$)&1%!#0!'/%!9)29%:F!!!

3. Validation Study

c/%.%!'/%!.%(+2'(!#0!)!8.#1%((!1)&&#'!3%!0+227!9%.-0-%*!37!(+3(%P+%&'!-&(8%1'-#&!)&*!'%('G!

)(!4-'/!0-&-(/%*!*%9-1%!('%.-2-g)'-#&G!'/%!8.#1%((!$+('!3%!9)2-*)'%*!4-'/!)!/-,/!*%,.%%!#0!

)((+.)&1%!?LK!"AJ!ML6:TEF:!c%!.%1#$$%&*!'/)'!7#+!(+3$-'!.%(+2'(!#0!)!9)2-*)'-#&!('+*7!

'#!(/#4!'/)'!'/%!('%.-2-g)'-#&!8.#1%((!8.#9-*%(!)!('%.-2-'7!)((+.)&1%!2%9%2!?;BIF!#0!)'!2%)('!

K6CHG!-:%:G!'/%!8.#3)3-2-'7!#0!0-&*-&,!)&!+&('%.-2-g%*!*%9-1%!-(!#&%!-&!#&%!$-22-#&:!!\/%!

9)2-*)'-#&!(/#+2*!-&12+*%!+(%!#0!-&#1+2)'%*!8.#*+1'!#.!-&*-1)'#.(!?3-#2#,-1)2!#.!#'/%.!

'78%(F!82)1%*!-&!'/%!2#1)'-#&!#0!'/%!*%9-1%!'/)'!-(!$#('!*-00-1+2'!'#!('%.-2-g%G!)&*!4-'/-&!'/%!

('%.-2-g)'-#&!1/)$3%.:!!Q-)32%!(8#.%!1#+&'!#&!3-#2#,-1)2!-&*-1)'#.(!(/#+2*!3%!9%.-0-%*!

3%0#.%!%)1/!+(%:!!\/%!#.,)&-($!1/#(%&!)(!'/%!-&*-1)'#.!(/#+2*!.%8.%(%&'!'/%!4#.('!1)(%!

#.,)&-($!0#.!'/%!8).'-1+2).!'78%!#0!('%.-2-g)'-#&!$%'/#*!1/#(%&:!!B22!%P+-8$%&'!+(%*!

*+.-&,!'/%!8.#1%((!'#!$#&-'#.!1#&*-'-#&(!?'/%.$#1#+82%(G!,)+,%(G!%'1:F!(/#+2*!/)9%!3%%&!

.%1%&'27!1)2-3.)'%*:!!<%$#&('.)'%!)&*!*#1+$%&'!'/)'!'/%!9)2-*)'-#&!$%'/#*(!1/#(%&!).%!

1#$8)'-32%!4-'/!'/%!*%9-1%!)&*!8)1=),-&,!$)'%.-)2(!'/+(!%(')32-(/-&,!'/%!/-,/!*%,.%%!#0!

)((+.)&1%:!

!

4. Controls

\/%!%&9-.#&$%&')2!1#&*-'-#&(!#0!7#+.!0)1-2-'7!1)&!.%)(#&)327!3%!%Y8%1'%*!'#!/)9%!)&!

)*9%.(%!%00%1'!#&!8.#*+1'!P+)2-'7:!!W#+!$+('!%(')32-(/!)&*!$)-&')-&!8.#1%*+.%(!'#!

)*%P+)'%27!1#&'.#2!'/%(%!%&9-.#&$%&')2!1#&*-'-#&(!?LK!"AJ!ML6:T6?1F!)&*!LK!"AJ!

ML6:T6?%FF:!c%!.%1#$$%&*!'/)'!7#+!-&12+*%!-&0#.$)'-#&!#&!'/%!1#&'.#2(!+(%*!'#!%&(+.%!

'/)'!'/%!3-#3+.*%&!#&!'/%!*%9-1%!-(!2#4!?%:,:G!'/%!12%)&-&,!(1/%*+2%!0#.!'/%!02##.(!)&*!

#'/%.!(+.0)1%(G!*-(-&0%1'-#&!8.#1%*+.%(G!$)&),%$%&'!#0!4)'%.!)&*!)-.!(7('%$(G!2)$-&).!

! 5


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

02#4!/##*(G!('%.-2-g%.(F:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!(8%1-07!'/%!4).&-&,!)&*!)1'-#&!

2-$-'(!0#.!3-#3+.*%&:!!!

!

5. Package Integrity

W#+!$+('!%&(+.%!'/)'!*%9-1%!8)1=),%(!).%!*%(-,&%*!)&*!1#&('.+1'%*!'#!8.#'%1'!'/%!*%9-1%!

0.#$!)2'%.)'-#&!#.!*)$),%G!-&12+*-&,!'/%!1#&')$-&)'-#&!#0!('%.-2%!*%9-1%(!?LK!"AJ!

ML6:KD6F:!!\%('-&,!(/#+2*!-&12+*%!)&!)((%(($%&'!#0!8)1=),%!-&'%,.-'7!?9-)!+(%!#0!)!

8/7(-1)2!$%'/#*G!(+1/!)(!)!2%)=!'%('G!#.!)!$-1.#3-)2!1/)22%&,%!0#22#4%*!37!('%.-2-'7!

)((%(($%&'!#0!'/%!1#&'%&'(F:!!c%!.%1#$$%&*!'/)'!7#+!'%('!'/%!0-&)2!4/#2%!8)1=),%!)0'%.!

(-$+2)'%*!#.!.%)2C'-$%!),-&,G!(/-8$%&'G!/)&*2-&,!)&*!%&9-.#&$%&')2!('.%((-&,:!!\%('-&,!

'/%!0-&)2!4/#2%!8)1=),%!-(!8.%0%..%*!#9%.!)((%((-&,!8)1=),%!1#$8#&%&'(!(%8).)'%27G!#.!

#&27!)((%((-&,!(%)2%*!).%)(:!!

!

XI. Preclinical In Vitro Assessment

_)(%*!#&!7#+.!.-(=!)&)27(-(G!4%!.%1#$$%&*!'/)'!7#+!8%.0#.$!8.%12-&-1)2!*5'6*,$1!'%('-&,!#&!7#+.!

.%82)1%$%&'!/%).'!9)29%!0#22#4-&,!'/%!$%'/#*(!*%(1.-3%*!-&!U;R!EMZ6NL66E!#.!%P+-9)2%&'!

$%'/#*(:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!8.#9-*%!%Y82)&)'-#&(!0#.!)&7!*5'6*,$1!'%('-&,!7#+!#$-':!!

W#+.!U<S!)&*![>B!)882-1)'-#&(!(/#+2*!-&12+*%!'/%!'%('!1#&*-'-#&(G!()$82%!(%2%1'-#&G!)&*!'%('!

.%8#.'(!0#.!'/%!0#22#4-&,N!

! $)'%.-)2!8.#8%.'7!'%('-&,!

! 3-#2#,-1)2!()0%'7!

! /7*.#*7&)$-1!8%.0#.$)&1%!

! ('.+1'+.)2!8%.0#.$)&1%!

! *%9-1%!*+.)3-2-'7!

! 1#$8#&%&'!0)'-,+%!)((%(($%&'(!

! *%9-1%!(8%1-0-1!'%('-&,:!

!

A#.!%)1/!'%('G!4%!.%1#$$%&*!'/)'!7#+.!'%('!.%8#.'!-&12+*%!'/%!8.#'#1#2G!)11%8')&1%!1.-'%.-)!)&*!

.%(+2'(!?%-'/%.!)(!*)')!#.!8)((O0)-2F:!!W#+.!8.#'#1#2!(/#+2*!-&12+*%!()$82%!(-g%G!%&9-.#&$%&')2!

1#&*-'-#&(G!'%('!8).)$%'%.(G!)&*!'%('!*+.)'-#&:!!B!')3+2).!0#.$)'!-(!*%(-.)32%G!(%%!'/%!%Y)$82%!

')32%!)'!'/%!%&*!#0!'/-(!(%1'-#&:!

!

U&!)**-'-#&G!*%(-,&!1#&'.#2(!)8827!'#!)22!/%).'!9)29%(:!!W#+!$+('!%(')32-(/!)&*!$)-&')-&!

8.#1%*+.%(!-&!#.*%.!'#!%&(+.%!'/)'!(8%1-0-%*!*%(-,&!.%P+-.%$%&'(!).%!$%'!?LK!"AJ!ML6:D6?)FF:!!

\/%(%!8.#1%*+.%(!$+('!-&12+*%!*%(-,&!9)2-*)'-#&!8.#1%*+.%(:!!<%(-,&!9)2-*)'-#&!$+('!%&(+.%!'/)'!

*%9-1%(!1#&0#.$!'#!*%0-&%*!+(%.!&%%*(!)&*!-&'%&*%*!+(%(!)&*!$+('!-&12+*%!'%('-&,!#0!8.#*+1'-#&!

+&-'(!+&*%.!)1'+)2!#.!(-$+2)'%*!+(%!1#&*-'-#&(:!!?;%%!LK!"AJ!ML6:D6?,FF:!!B11#.*-&,27G!4%!

.%1#$$%&*!'/)'!7#+!-&12+*%!'/%!-&0#.$)'-#&!*%(1.-3%*!3%2#4!-&!7#+.!U<S!#.![>B!)882-1)'-#&:!!!

!

!

! K6

cris

cris


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

A. Valve Samples

c%!.%1#$$%&*!'/)'!7#+!8%.0#.$!)22!*5'6*,$1!'%('(!#&!0-&-(/%*!9)29%(G!#0!'/%!0-&)2!*%(-,&G!

%Y8#(%*!'#!'/%!$)Y-$+$!&+$3%.!#0!.%1#$$%&*%*!('%.-2-g)'-#&!1712%(:!

!

B. Reference Valves

A#.!)&7!'%('!'/)'!*#%(!&#'!/)9%!9)2-*)'%*!8)((O0)-2!1.-'%.-)G!4%!.%1#$$%&*!'/)'!7#+!-&12+*%!

'/%!+(%!#0!)!2%,)227!$).=%'%*!.%0%.%&1%!/%).'!9)29%!#0!(-$-2).!1#$8#(-'-#&!)(!'/%!9)29%!7#+!

).%!'%('-&,:!

!

C. Biocompatibility

A<B!.%1#$$%&*(!'/)'!7#+!1#&*+1'!3-#1#$8)'-3-2-'7!'%('-&,!)(!*%(1.-3%*!-&!'/%!A<B!

,+-*)&1%G!Use of International Standard ISO-10993, Biological Evaluation of Medical

Devices Part-1: Evaluation and TestingGM!0#.!32##*C1#&')1'-&,G!2#&,C'%.$!-$82)&'%*!

*%9-1%(:!!U0!7#+!0#22#4!)!9#2+&').7!(')&*).*!'/)'!-(!.%2%9)&'!'#!)&7!)(8%1'!#0!'/%!()0%'7!#.!

%00%1'-9%&%((!#0!'/%!*%9-1%!'/)'!-(!=&#4&G!#.!'/)'!(/#+2*!.%)(#&)327!3%!=&#4&G!'#!7#+G!7#+!

$+('!%Y82)-&!)&7!*%9-)'-#&!0.#$!(+1/!(')&*).*!?LK!"AJ!MKZ:L6!?3F?EF?--FF:!!>)'%.-)2C

$%*-)'%*!87.#,%&-1-'7!'%('-&,!+(-&,!'/%!.)33-'!87.#,%&!'%('!(/#+2*!3%!8%.0#.$%*!)(!8).'!#0!'/%!

3-#1#$8)'-3-2-'7!3)''%.7!#0!'%('-&,:!!B!')3+2).!0#.$)'!-(!*%(-.)32%G!)(!(/#4&!3%2#4: !

!

Biocompatibility Information – Tabular Format Example!TEST PERFORMED/

LAB REPORT #

(literature citation, standard reference)

EXTRACT(S) IF USED

(polar, non-polar), or animal model/cell line

EXTRACT CONDITIONS

(time, temperature, area or mass to volume

ratio compared to in-use conditions)

TEST AND CONTROL(S)

USED

RESULTS/COMMENTS

(include units when appropriate, and include

descriptions for all deviations from the standard/protocol

Cytotoxicity

Sensitization

Irritation / Intracutaneous Toxicity

Systemic toxicity

Sub-chronic toxicity

Genotoxicity

gene mutation

chromosome aberration

DNA damage

In vivo assay

Implantation

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!M!\/-(!,+-*)&1%!*#1+$%&'!1)&!3%!#3')-&%*!)'N!

/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$6

M6TDE:/'$! !

! KK

cris




-$%.,'/'01,'.1$'234&"3"5,%,*15'

!Hemocompatibility

hemolysis

complement

activation

in vivo thrombogenicity*

Pyrogenicity

Chronic toxicity

Carcinogenicity

Biodegradation

Reproductive or Developmental toxicity

*You may assess thrombogenicity in animal studies in place of this test.

D. Valve Durability Testing

c%!.%1#$$%&*!'/)'!7#+!)((%((!'/%!*+.)3-2-'7!#0!.%82)1%$%&'!/%).'!9)29%(!+(-&,!)11%2%.)'%*!

4%).!'%('-&,!?Bc\F!$%'/#*(!*-(1+((%*!-&!U;R!EMZ6NL66E!#.!%P+-9)2%&'!$%'/#*(:!!Bc\!

(/#+2*!1#&'-&+%!0#.!H66!$-22-#&!1712%(!0#.!.-,-*!9)29%(!)&*!L66!$-22-#&!1712%(!0#.!02%Y-32%!

9)29%(G!+(-&,!)!3)1=!8.%((+.%!3%'4%%&!KLE!)&*!KE6!$$@,G!'#!'%('!'/%!*+.)3-2-'7!#0!'/%!

1#$8#&%&'(!+&*%.!8+2()'-2%!02#4!)&*!8/7(-#2#,-1!2#)*-&,:!!c%!.%1#$$%&*!'/)'!7#+!0+227!

*%(1.-3%!)22!1#&*-'-#&(!*+.-&,!Bc\G!-&12+*-&,!.)'-#&)2%!0#.!'/%!1#&*-'-#&(!1/#(%&G!0#.!'/%!

0#22#4-&,N!

! '/%!02+-*!+(%*!!! '/%!02#4!.)'%(!'/.#+,/!'/%!9)29%(!!! '/%!8.%((+.%!2#)*-&,!-&12+*-&,!3)1=!8.%((+.%:!

!

E. Component Fatigue Testing

"#$8#&%&'(!#0!.-,-*!.%82)1%$%&'!/%).'!9)29%(!)&*!'/%!2#)*!3%).-&,G!&#&C3-#2#,-1)2!

1#$8#&%&'(!#0!02%Y-32%!.%82)1%$%&'!/%).'!9)29%(!?%:,:G!('%&'!4-.%F!(/#+2*!3%!-&*-9-*+)227!

0)'-,+%!'%('%*!'#!H66!$-22-#&!1712%(:!!!

!

F. Dynamic Failure Mode Testing

c%!.%1#$$%&*!'/)'!7#+!(+3l%1'!)!(%2%1'-#&!#0!9)29%(!'/)'!/)9%!(+.9-9%*!'/%!Bc\!'#!

)**-'-#&)2!'%('(!'#!*%'%.$-&%!'/%!$#*%!-&!4/-1/!'/%!9)29%(!4-22!0)-2:!!c%!.%1#$$%&*!'/)'!7#+!

8.#9-*%!P+)2-')'-9%!)&*!P+)&'-')'-9%!)((%(($%&'(!#0!'/%!0)-2+.%!$#*%(!)&*!/-,/!('.%((!).%)(!-&!

'/%!9)29%!?-:%:G!$#*%!)&*!2#1)'-#&!#0!'/%!0)-2+.%F:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!+(%!'/%(%!

.%(+2'(!'#!(+88#.'!)&7!)&)27'-1)2!9)2-*)'-#&!#.!1#$8+')'-#&)2!$#*%2-&,!#0!('.%((!)&)27(%(!#0!

'/%!1#$8#&%&'(:!

!

G. Cavitation

c%!.%1#$$%&*!'/)'!7#+!8%.0#.$!1)9-')'-#&!'%('-&,!#0!.-,-*!/%).'!9)29%(!)(!*%(1.-3%*!-&!

B88%&*-Y!_:!

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!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

H. Corrosion Resistance

c%!.%1#$$%&*!'/)'!7#+!*%'%.$-&%!'/%!1#..#(-#&!.%(-(')&1%!#0!'/%!$%')22-1!$)'%.-)2(!37!

'%('-&,!'/%!0-&)2!0-&-(/%*!*%9-1%!-&!)!8/7(-#2#,-1)2!%&9-.#&$%&'!)&*G!-0!)88.#8.-)'%G!+&*%.!

('.%((:!!U0!7#+!8%.0#.$!'%('-&,!+&*%.!1712-1!2#)*-&,G!4%!.%1#$$%&*!'/)'!7#+!1#&*+1'!'%('(!

+&*%.!'/%!()$%!'78%!#0!2#)*-&,!)'!)!0.%P+%&17!'/)'!4-22!&#'!$)(=!2#1)2-g%*!)'')1=:!!c%!

.%1#$$%&*!'/)'!7#+!8%.0#.$!1#..#(-#&!'%('-&,!3#'/!3%0#.%!)&*!)0'%.!7#+.!0)'-,+%!'%('-&,:!!

c%-,/'!2#((!$%'/#*(!(/#+2*!&#'!3%!+(%*!'#!%9)2+)'%!2#1)2-g%*!)'')1=!?%:,:G!8-''-&,F!+&2%((!7#+!

).%!)32%!'#!%(')32-(/!'/)'!7#+.!%Y8%.-$%&')2!'%1/&-P+%!-(!(+00-1-%&'27!(%&(-'-9%:!!c%!

.%1#$$%&*!'/)'!7#+!1#&*+1'!)22!1#..#(-#&!'%('-&,!#&!0-&)2!0-&-(/%*!8.#*+1':!!!

!

I. Flammability of Valved Conduits

U0!7#+.!2)3%2-&,!.%1#$$%&*(!+(-&,!)&!%2%1'.#1)+'%.7!*%9-1%!'#!1+'!'/%!1#&*+-'!$)'%.-)2G!7#+!

(/#+2*!)((%((!'/%!02)$$)3-2-'7!#0!'/%!1#&*+-':!!!

!

J. Hemodynamic Performance - Verification of the Bernoulli

Relationship

c%!.%1#$$%&*!'/)'!7#+!)((%((!'/%!12-&-1)2!/%$#*7&)$-1!8%.0#.$)&1%!37!<#882%.!

+2'.)(#+&*G!+(-&,!'/%!_%.&#+22-!.%2)'-#&(/-8G!

!

![!n!]?Q*L!C!Q8

LF!

!

4/%.%N!!

]!-(!)!1#&(')&'!

![!-(!'/%!8.%((+.%!,.)*-%&'!

Q*!-(!'/%!*-(')2!9%2#1-'7!$%)(+.%*!37!1#&'-&+#+(!4)9%!<#882%.!

Q8!-(!'/%!8.#Y-$)2!9%2#1-'7!$%)(+.%*!37!8+2(%*!<#882%.!!!

!

\/%!9)2+%!#0!'/%!1#&(')&'!]!1)&!9).7!*%8%&*-&,!#&!9)29%!'78%:!!;%%!Appendix C. Bernoulli

Verification!0#.!)**-'-#&)2!.%1#$$%&*)'-#&(:!!

!

K. Magnetic Resonance (MR) Safety Testing

A#.!-&0#.$)'-#&!.%,).*-&,!>),&%'-1!J%(#&)&1%!?>JF!()0%'7!'%('-&,G!82%)(%!(%%!A<B!

,+-*)&1%!*#1+$%&'!%&'-'2%*G!hS(')32-(/-&,!;)0%'7!)&*!"#$8)'-3-2-'7!#0![)((-9%!U$82)&'(!-&!

'/%!>),&%'-1!J%(#&)&1%!?>JF!S&9-.#&$%&':i5!!

!

;%%!)2(#!XVI. Professional Labeling:!

!5!!\/-(!,+-*)&1%!*#1+$%&'!1)&!3%!#3')-&%*!)'N!

/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1

$K6TT6E:/'$!0#.!,+-*)&1%!#&!>J!()0%'7!'%('-&,!#0!7#+.!*%9-1%:!!!!!!!

! KD




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!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

!

L. Shelf Life

c%!.%1#$$%&*!'/)'!7#+!8%.0#.$!'/%!(/%20!2-0%!('+*-%(!*%(1.-3%*!-&!B88%&*-Y!B!#0!'/-(!

,+-*)&1%:!

!

XII. Preclinical Animal Studies

A<B!.%1#$$%&*(!'/)'!)&-$)2!('+*-%(!3%!1#&*+1'%*!'#!%9)2+)'%!$#('!&%4!.%82)1%$%&'!/%).'!

9)29%!*%(-,&(!)&*!'/)'!'/%(%!('+*-%(!$)..7!3%('!8.)1'-1%(!#0!3-#$%*-1)2!.%(%).1/G!-&12+*-&,!

#3(%.9)&1%!#0!DJ!8.-&1-82%(!?-:%:G!.%*+1%G!.%0-&%G!#.!.%82)1%FG!4/%&%9%.!-'!4-22!&#'!1#$8.#$-(%!'/%!

-&9%('-,)'-#&!#0!()0%'7:K6!!\/%.%0#.%G!4%!.%1#$$%&*!'/)'!7#+!8%.0#.$!*5'6*61!)&-$)2!'%('-&,!#&!

7#+.!.%82)1%$%&'!/%).'!9)29%!0#22#4-&,!'/%!$%'/#*(!*%(1.-3%*!-&!U;R!EMZ6NL66E!)&*!U;R!

K655DNL66H!#.!%P+-9)2%&'!$%'/#*(:!!U0!7#+!+(%!*-00%.%&'!%&*8#-&'(!#.!*%9-)'%!0.#$!'/%!'%('-&,!

*%(1.-3%*!-&!'/-(!,+-*)&1%!#.!)!(')&*).*!7#+!0#22#4G!4%!.%1#$$%&*!'/)'!7#+!%Y82)-&!4/7!7#+.!

)88.#)1/!-(!(1-%&'-0-1)227!9)2-*:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!8.#9-*%!%Y82)&)'-#&(!0#.!)&7!*5'

6*61!)&-$)2!'%('-&,!7#+!#$-':!![.-#.!'#!8%.0#.$-&,!)&-$)2!('+*-%(G!7#+!$)7!4)&'!'#!#3')-&!A<B!

-&8+'!#&!7#+.!)&-$)2!('+*7!8.#'#1#2!9-)!'/%!8.%C(+3$-((-#&!8.#1%((:!!W#+.!&#&12-&-1)2!2)3#.)'#.7!

('+*-%(!$+('!3%!1#&*+1'%*!-&!)11#.*)&1%!4-'/!LK!"AJ![).'!EMG!V##*!I)3#.)'#.7![.)1'-1%!0#.!

^#&12-&-1)2!I)3#.)'#.7!;'+*-%(:!!c%!.%0%.!7#+!'#!'/#(%!.%,+2)'-#&(!0#.!1#$8.%/%&(-9%!.%,+2)'-#&!

#0!V##*!I)3#.)'#.7![.)1'-1%G!3+'!*-(1+((!(%9%.)2!)(8%1'(!#0!)&-$)2!('+*-%(!/%.%:!

!

A. Methods

U0!'%1/&-1)227!0%)(-32%G!4%!.%1#$$%&*!1/.#&-1!)((%(($%&'!#0!7#+.!.%82)1%$%&'!/%).'!9)29%!-&!

)22!)&)'#$-1)2!8#(-'-#&(!.%02%1'%*!-&!'/%!-&*-1)'-#&(!0#.!+(%:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!

%Y82)-&!7#+.!.)'-#&)2%!0#.!'/%!)&-$)2!$#*%2!7#+!/)9%!(%2%1'%*:!!U;R!EMZ6NL66E!,%&%.)227!

.%1#$$%&*(!+(-&,!#&27!'/%!()$%!(8%1-%(G!)&*!(+,,%('(!+(-&,!)&-$)2(!#0!'/%!()$%!,%&*%.!)&*!

),%!-&!)&-$)2!('+*-%(k!/#4%9%.G!4%!3%2-%9%!'/-(!$)7!&#'!3%!)*%P+)'%!'#!%9)2+)'%!)22!)1+'%!)&*!

1/.#&-1!('+*-%(!#0!)!&%4!9)29%!*%(-,&:!!\/%.%0#.%G!4%!$)7!.%1#$$%&*!)**-'-#&)2!)&-$)2!

'%('-&,!3%7#&*!'/)'!*%(1.-3%*!-&!U;R!EMZ6NL66E:!!!

!

B. Study Design

c%!.%1#$$%&*!'/)'!7#+!%9)2+)'%!'/%!0-&)2!0-&-(/%*!8.#*+1'!-&!7#+.!)&-$)2!('+*-%(:!!c%!

.%1#$$%&*!'/)'!7#+!)((%((!'/%!)&-$)2!)&*!'/%!*%9-1%!-$$%*-)'%27!)0'%.!-$82)&')'-#&!?)1+'%!

/%$#*7&)$-1!8%.0#.$)&1%k!-$82)&')'-#&!/)&*2-&,!1/).)1'%.-('-1(F!)&*!)'!L6!4%%=(!?1/.#&-1!

/%$#*7&)$-1!8%.0#.$)&1%k!%Y82)&'!8)'/#2#,7F:!!c%!$)7G!/#4%9%.G!.%1#$$%&*!'/)'!7#+.!

1/.#&-1!('+*7!1#&'-&+%!$#.%!'/)&!L6!4%%=(G!-0!'/%!.-(=!)((%(($%&'!#0!7#+.!*%9-1%!-&*-1)'%(!

'/)'!)!,.%)'%.!*+.)'-#&!-(!)88.#8.-)'%:!!c%!)2(#!.%1#$$%&*!'/)'!7#+.!('+*-%(!1#&(-('!#0!)!

!K6!;%%![+32-1!@%)2'/!;%.9-1%![#2-17!#&!@+$)&%!").%!)&*!`(%!#0!I)3#.)'#.7!B&-$)2(:!!

/''8NOO,.)&'(:&-/:,#9O,.)&'(O#2)4O.%0%.%&1%(O8/(8#2:/'$m@%)2'/oL6J%(%).1/oL6SY'%&(-#&oL

6B1'oL6#0oL6K5ME! !!! !!

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http://grants.nih.gov/grants/olaw/references/phspol.htm#Health%20Research%20Extension%20Act%20of%201985

http://grants.nih.gov/grants/olaw/references/phspol.htm#Health%20Research%20Extension%20Act%20of%201985


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

C.

8.#(8%1'-9%27C*%0-&%*!&+$3%.!#0!)&-$)2(!0#.!'/%!)1+'%G!1/.#&-1!)&*!1#&'.#2(!).$(!#0!7#+.!

('+*7:!!c%!.%1#$$%&*!'/)'!)!.)'-#&)2%!0#.!(%2%1'-#&!#0!'/%!&+$3%.!#0!)&-$)2(!3%!8.#9-*%*:!!!

!

R+.!V##*!I)3#.)'#.7![.)1'-1%!.%,+2)'-#&(!.%P+-.%!'/)'G!0#.!%)1/!('+*7G!7#+!$+('!/)9%!)&!

)88.#9%*!4.-''%&!8.#'#1#2!'/)'!12%).27!-&*-1)'%(!'/%!#3l%1'-9%(!)&*!)22!$%'/#*(!0#.!'/%!

1#&*+1'!#0!'/%!('+*7!?LK!"AJ!EM:KL6?)FF:!

!

c%!)2(#!.%1#$$%&*!)((%(($%&'!#0!)1+'%!)&*!1/.#&-1!/%$#*7&)$-1!8%.0#.$)&1%G!9)29%C

.%2)'%*!8)'/#2#,7!-&!%-'/%.!)&!#.'/#'#8-1!#.!&#&C#.'/#'#8-1!8#(-'-#&G!)&*!1/.#&-1!8%.0#.$)&1%!

#0!)&'-1)21-0-1)'-#&!'.%)'$%&'(!?-0!)882-1)32%F:!!U&!)**-'-#&G!4%!.%1#$$%&*!L6!#.!$#.%!4%%=(!

#0!0#22#4C+8!0#.!1/.#&-1!-$82)&')'-#&:!

!

Data Collection

c%!.%1#$$%&*!'/)'!7#+!1#22%1'!'/%!*)')!2-('%*!3%2#4:!

!

1. Study of Acute Hemodynamic Performance

U&!7#+.!)1+'%!('+*7G!4%!.%1#$$%&*!'/)'!7#+!1#22%1'N!!

! %)(%!#0!/)&*2-&,!)&*!(+.,-1)2!-$82)&')'-#&!!

! /%$#*7&)$-1!8%.0#.$)&1%!?1)'/%'%.!*)')!)(!4%22!)(!%1/#1).*-#,.)8/7F!

! 2%)02%'!$#'-#&!?37!%1/#1).*-#,.)8/7!)&*!)&,-#,.)8/7F!

! 8.%(%&1%!#0!('%&#(-(!#.!.%,+.,-')'-#&:!!!

!

2. Study of Chronic Hemodynamic Performance

U&!7#+.!1/.#&-1!('+*7G!4%!.%1#$$%&*!'/)'!7#+!1#22%1'N!!

! %)(%!#0!/)&*2-&,!)&*!(+.,-1)2!-$82)&')'-#&!!

! /%$#*7&)$-1!8%.0#.$)&1%!?1)'/%'%.!*)')!)(!4%22!)(!%1/#1).*-#,.)8/7F!

! 2%)02%'!$#'-#&!?37!%1/#1).*-#,.)8/7!)&*!)&,-#,.)8/7F!!

! 8.%(%&1%!#0!('%&#(-(!#.!.%,+.,-')'-#&!

! 32##*!('+*-%(G!-$),-&,!('+*-%(!#0!2%)02%'!$#'-#&!)&*!.%,+.,-')'-#&!!

! *5'+*,8'8/#'#(!#0!-&02#4!)&*!#+'02#4!.%,-#&(!)&*!9)29%!(+.0)1%(!!

! &%1.#8(7!)&*!,.#((!8)'/#2#,7!

! %Y82)&'%*!9)29%!)&)27(-(!?-&12+*-&,!/-('#2#,7!#0!'/%!9)29%!)&*!(+..#+&*-&,!'-((+%F:!

!

3. Hemodynamic Performance Assessment

A#.!'/%!/%$#*7&)$-1!8%.0#.$)&1%!)((%(($%&'G!4%!.%1#$$%&*!'/)'!7#+!-&12+*%N!!

! 8%)=!)&*!$%)&!8.%((+.%!,.)*-%&'!

! %00%1'-9%!#.-0-1%!).%)!?SRBF!.%,+.,-')'-#&!

! )!*%(1.-8'-#&!#0!-&('.+$%&')'-#&!)&*!'%('!$%'/#*(:!!!

!

! KE


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!

D.

4. Laboratory Results

"#$82%'%!32##*!1#+&'!?"_"F!)&*!1/%$-('.7!)&)27(-(!(/#+2*!-&12+*%N!!

! .%*!32##*!1%22!1#+&'!

! 4/-'%!32##*!1%22!1#+&'!?4-'/!*-00%.%&'-)2F!

! /%$)'#1.-'!

! 0.%%!/%$#,2#3-&!

! (%.+$!2)1')'%!*%/7*.#,%&)(%!

! /)8'#,2#3-&!

! .%'-1+2#17'%!1#+&'!

! 82)'%2%'!1#+&':!

!

A#.!02%Y-32%!2%)02%'!9)29%(G!-&!)**-'-#&!'#!'/%!'%('(!2-('%*!)3#9%G!7#+!(/#+2*!-&12+*%N!

! (%.+$!1)21-+$!

! (%.+$!8/#(8/#.#+(!

! 2%)02%'!1)21-+$!

! 8/#(8/)'%:!!!

!

Data Analysis

U&!)**-'-#&!'#!'/%!-&0#.$)'-#&!*%(1.-3%*!-&!U;R!EMZ6NL66EG!7#+.!'%('!.%8#.'!(/#+2*!-&12+*%N!!!

! )88%&*-1%(!4-'/!12-&-1)2!)&*!/%$)'#2#,-1)2!2)3#.)'#.7!.%(+2'(!

! /%$#*7&)$-1!0-&*-&,(!

! '/%!0-&)2!8)'/#2#,7!.%8#.'!?-&12+*-&,!,.#((!8)'/#2#,7!4-'/!$)1.#(1#8-1!8/#'#,.)8/(G!

.)*-#,.)8/(G!('.+1'+.)2!-&'%,.-'7!)((%(($%&'!0#.!.-,-*!)&*!8%.1+')&%#+(!*%2-9%.%*!

9)29%(G!)&*!/-('#8)'/#2#,7!4-'/!.%8.%(%&')'-9%!$-1.#,.)8/(F!

!

E. Final Report of Animal Study

W#+!$+('!8.%8).%!)!0-&)2!.%8#.'!0#.!%)1/!&#&12-&-1)2!2)3#.)'#.7!('+*7!?LK!"AJ!EM:KMEF:!!

B$#&,!#'/%.!'/-&,(G!7#+.!0-&)2!.%8#.'!$+('!-*%&'-07!)&*!*%(1.-3%!'/%!'%('!)&*!1#&'.#2!*%9-1%!

7#+!+(%*!-&!'/%!)&-$)2!('+*-%(!?LK!"AJ!EM:KME?)F?ZFF:!!!

!

W#+!$+('!)2(#!-&12+*%!'/%!&+$3%.(!#0!)&-$)2(!+(%*!'#!#3')-&!'/%(%!*)')!?LK!"AJ!

EM:KME?)F?TFF:!

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\#!$%%'!'/%!0-&)2!.%8#.'!.%P+-.%$%&'(G!'/%!.%8#.'!$+('!-&12+*%N

! 9)29%!$#*%2?(F!

! 9)29%!(-g%?(F!

! 4/%'/%.!'/%!*%9-1%!4)(!('%.-2%!#.!&#&C('%.-2%!

! 4/%'/%.!'/%!*%9-1%!4)(!),%*!3%0#.%!-$82)&')'-#&!

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! 1#&'.#2!*%9-1%!!

! -$82)&'!2#1)'-#&:!

!

\/%!0-&)2!.%8#.'!(/#+2*!)2(#!*%(1.-3%!)&-$)2!0#22#4!+8:!!\/%!*%(1.-8'-#&!(/#+2*!-&12+*%!

0.%P+%&17G!*+.)'-#&G!)&*!%9)2+)'-#&!$%'/#*?(F:!

!

W#+.!.%8#.'!(/#+2*!*%0-&%!0)-2+.%(!?%:,:G!*%9-1%!0)-2+.%(!(+1/!)(!2%)02%'!'%).G!('%&'!0.)1'+.%G!

3)22##&!.+8'+.%F:!!W#+!(/#+2*!-&*-1)'%!'/%!'#')2!&+$3%.!#0!*%9-1%!0)-2+.%(!)&*!-&12+*%!)!

1#$82%'%!*%(1.-8'-#&!0#.!%)1/:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!%Y82)-&!)&7!8.#1%*+.)2!0)-2+.%(!

(+1/!)(!9)29%!$-()2-,&$%&'G!-$8.#8%.!(+'+.-&,G!#.!(-g%!$-($)'1/G!)&*!'/)'!7#+!8.#9-*%!)!

1#$82%'%!*%(1.-8'-#&!#0!%)1/:!!\/%!.%8#.'!(/#+2*!(/#4!'/%!'#')2!&+$3%.!#0!0)-2+.%(G!('.)'-0-%*!

37!7#+.!*%0-&-'-#&(:

!

W#+.!'%('!.%8#.'!$+('!-&12+*%!)!*%(1.-8'-#&!#0!)22!1-.1+$(')&1%(!'/)'!$)7!/)9%!)00%1'%*!'/%!

P+)2-'7!#.!-&'%,.-'7!#0!'/%!*)')G!-&12+*-&,!)!2-('-&,!#0!)22!8.#'#1#2!*%9-)'-#&(!)&*!'/%-.!-$8)1'!

#&!('+*7!0-&*-&,(!?LK!"AJ!EM:KME?)F?5FF:!!!

!

F. Submitting Animal Study Information to your IDE and

PMA

W#+!$+('!(+3$-'!7#+.!0-&)2!.%8#.'!#0!)22!)&-$)2!('+*-%(!'#!7#+.!U<S!)&*![>B!?MKL:LT?)FG!

MKZ:L6?3F?HF?-FF: W#+!(/#+2*!8.#9-*%!0#.!%)1/!('+*7N!

! ('+*7!*)'%(!

! %&*8#-&'(!!

! 0)-2+.%!)&*!(+11%((!1.-'%.-)!

! 8/7(-#2#,-1)2!.%(8#&(%(!'%('%*!?%:,:G!1).*-)1!#+'8+'!?"RFF!!!

! )&7!-&#'.#8-1!*.+,!)*$-&-('%.%*!?)&*!*#(%F!

! )&-$)2!$#*%2?(F!%$82#7%*!

! &+$3%.!#0!)&-$)2(!+(%*!

! )&-$)2!),%!)&*!9%.-0-1)'-#&!?-0!3-.'/!.%1#.*(!).%!&#'!)9)-2)32%G!4%!.%1#$$%&*!+(-&,!

*%&')2!%.+8'-#&!'-$%!)&*!$#.8/#2#,-1)2!1/)&,%(!#0!'/%!*%&')2!')32%F!

! $%*-1)'-#&(!)&*!*#(%(!,-9%&!0#.!8.%C8.#1%*+.%G!*+.-&,!8.#1%*+.%G!)&*!8#('C

8.#1%*+.%:!

c%!)2(#!.%1#$$%&*!'/)'!7#+!%Y82)-&!/#4!'/%!)&-$)2!$#*%2(!)&*!$%*-1)'-#&(!)*%P+)'%27!

.%8.%(%&'!'/%!-&'%&*%*!8)'-%&'!8#8+2)'-#&!)&*!)&'-1-8)'%*!12-&-1)2!%Y8%.-%&1%:!

!

U0!'/%!*%9-1%!7#+!-&'%&*!'#!$).=%'!*-00%.(!0.#$!'/%!9%.(-#&!+(%*!-&!'/%!)&-$)2!('+*-%(G!4%!

.%1#$$%&*!'/)'!7#+!*%(1.-3%!)22!1/)&,%(!-&!*%(-,&!)&*!$)&+0)1'+.-&,!0#22#4-&,!'/%!('+*-%(!

)&*!'/)'!7#+!8.#9-*%!)!.)'-#&)2%!'#!(+88#.'!+(-&,!)!*%9-1%!'/)'!-(!*-00%.%&'!0.#$!'/%!#&%!'/)'!-(!

-&'%&*%*!'#!3%!$).=%'%*:!

!

! KT


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

XIII. Clinical Investigations

"2-&-1)2!('+*-%(!).%!&%1%(().7!'#!%9)2+)'%!$#('!&%4!.%82)1%$%&'!/%).'!9)29%!*%(-,&(:!!c%!

.%1#$$%&*!'/)'!7#+!8%.0#.$!12-&-1)2!-&9%('-,)'-#&(!#0!7#+.!.%82)1%$%&'!/%).'!9)29%!0#22#4-&,!

'/%!$%'/#*(!*%(1.-3%*!-&!U;R!EMZ6NL66E!#.!%P+-9)2%&'!$%'/#*(:!![.-#.!'#!(+3$-''-&,!7#+.!U<S!

)882-1)'-#&G!7#+!$)7!4)&'!'#!#3')-&!A<B!-&8+'!#&!7#+.!12-&-1)2!('+*7!8.#'#1#2!9-)!'/%!8.%C

(+3$-((-#&!8.#1%((:!

!

[2%)(%!(%%!B88%&*-Y!<!#0!'/-(!,+-*)&1%!0#.!)**-'-#&)2!.%1#$$%&*)'-#&(!)3#+'!%1/#1).*-#,.)8/7!

4/%&!+(%*!-&!'/%!12-&-1)2!%9)2+)'-#&!#0!.%82)1%$%&'!/%).'!9)29%(:!!\/%!8.#'#1#2!(+3$-''%*!-&!7#+.!

U<S!)&*!'/%!0-&)2!12-&-1)2!.%8#.'!(+3$-''%*!-&!7#+.![>B!)882-1)'-#&(!(/#+2*!)**.%((!'/%!-((+%(!

*%(1.-3%*!3%2#4:!

!

A. Data Safety Monitoring Board

;8#&(#.(!).%!.%(8#&(-32%!0#.!%&(+.-&,!8.#8%.!$#&-'#.-&,!#0!'/%!-&9%('-,)'-#&!)&*!$+('!(%2%1'!

$#&-'#.(!P+)2-0-%*!37!'.)-&-&,!)&*!%Y8%.-%&1%!?LK!"AJ!MKL:Z6!)&*!LK!"AJ!MKL:ZD?*FF:!c%!

.%1#$$%&*!'/)'!7#+!%(')32-(/!)!<)')!;)0%'7!>#&-'#.-&,!_#).*!?<;>_FKK!'#!.%9-%4!)*9%.(%!

%9%&'(!)&*!.%1#$$%&*!('+*7!'%.$-&)'-#&!-0!()0%'7!1#&1%.&(!4)..)&':!!\/%!<;>_!(/#+2*!

%(')32-(/!1.-'%.-)!0#.!.%1#$$%&*-&,!('+*7!'%.$-&)'-#&!0#.!()0%'7!.%)(#&(!3%0#.%!'/%!('+*7!

3%,-&(!)&*!(/#+2*!$%%'!)'!2%)('!'4#!'-$%(!*+.-&,!'/%!('+*7!'#!$#&-'#.!)*9%.(%!%9%&'(:!!\/%!

<;>_!(/#+2*!/)9%!$%$3%.(!4/#!).%!-&*%8%&*%&'!0.#$!'/%!('+*7!(8#&(#.(!)&*!

-&9%('-,)'#.(:!!\4#!#.!$#.%!$%$3%.(!(/#+2*!3%!8/7(-1-)&(G!-&12+*-&,!)!1).*-#'/#.)1-1!

(+.,%#&!)&*!)!1).*-#2#,-(':!!U0!'/%!('+*7!-&12+*%(!(')'-('-1)2!)&)27(%(G!#&%!$%$3%.!(/#+2*!3%!)!

(')'-('-1-)&:!

!

B. Clinical Events Committee

c%!.%1#$$%&*!'/)'!7#+!%(')32-(/!)!"2-&-1)2!S9%&'(!"#$$-''%%!?"S"F!0#.!'/%!12-&-1)2!

-&9%('-,)'-#&!-&!#.*%.!'#!)*l+*-1)'%!)*9%.(%!%9%&'(!)(!3%-&,!9)29%C.%2)'%*!#.!&#'G!)&*!'#!

12)((-07!'/%!(%9%.-'7!#0!)*9%.(%!%9%&'(:!!\/%!"S"!(/#+2*!/)9%!$%$3%.(!4/#!).%!-&*%8%&*%&'!

0.#$!'/%!('+*7!(8#&(#.(!)&*!-&9%('-,)'#.(:!

!

C. Number of Investigators

U0!7#+.!('+*7!+(%(!#&27!#&%!12-&-1)2!-&9%('-,)'#.G!4%!.%1#$$%&*!'/)'!7#+!8.#9-*%!7#+.!

.)'-#&)2%!'#!(/#4!4/7!%Y8%.-%&1%!0.#$!'/-(!#&%!12-&-1)2!-&9%('-,)'#.!-(!(+00-1-%&'!'#!

*%$#&('.)'%!'/%!()0%'7!)&*!%00%1'-9%&%((!#0!7#+.!*%9-1%!)&*!'#!%&(+.%!.%8.#*+1-3-2-'7!#0!'%('!

.%(+2'(!)1.#((!$+2'-82%!*%9-1%!+(%.(:!

!

!

!

!KK!;%%!V+-*)&1%!0#.!12-&-1)2!'.-)2!(8#&(#.(!#&!:+,%;&*+73"5,'%5#'<4"$%,*15'1.'=&*5*>%&'?$*%&'-%,%'

@15*,1$*5)'=133*,,""+G!>).1/!L66H:!!

/''8NOO444:0*):,#9OJ%,+2)'#.7U&0#.$)'-#&OV+-*)&1%(O+1$KLT6H5:/'$:! !

! KM

http://www.fda.gov/RegulatoryInformation/Guidances/ucm127069.htm


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

D. Investigational Sites

U&9%('-,)'-#&)2!(-'%(!).%!)22!'/%!1%&'%.(!-$82)&'-&,!'/%!9)29%!-&!'/%!`&-'%*!;')'%(G!)&*!)22!'/%!

0#.%-,&!1%&'%.(!-$82)&'-&,!'/%!9)29%!'/)'!(+3$-'!*)')!)(!8).'!#0!'/%!-&9%('-,)'-#&:!!B22!(+3l%1'(!

(/#+2*!3%!1#$82%'%27!)11#+&'%*!0#.!-&!'/%!0-&)2!12-&-1)2!.%8#.':!!c%!.%1#$$%&*!'/)'!7#+!

8.#9-*%!1#$82%'%!(+3l%1'!)11#+&'-&,!#&!)!8%.!(+3l%1'!3)(-(!0#.!%)1/!1#/#.':!!W#+!(/#+2*!

-&12+*%!'/%!&+$3%.!#0!(+3l%1'(!%Y8%1'%*!0#.!0#22#4C+8G!*-(1#&'-&+%*!3%1)+(%!#0!*%)'/!#.!

*%9-1%!.%$#9)2G!)&*!)1'+)227!%9)2+)'%*!)'!%)1/!%9)2+)'-#&!'-$%!8#-&':!!!

!

E. Data Collection

\/%!(8#&(#.!4/#!*-(1#9%.(!'/)'!)&!-&9%('-,)'#.!-(!&#'!1#$827-&,!4-'/!'/%!(-,&%*!),.%%$%&'G!

'/%!-&9%('-,)'-#&)2!82)&G!.%P+-.%$%&'(!-&!LK!"AJ![).'!MKL!#.!#'/%.!)882-1)32%!A<B!

.%,+2)'-#&(G!#.!)&7!1#&*-'-#&(!#0!)88.#9)2!-$8#(%*!37!'/%!.%9-%4-&,!-&9%('-,)'-#&)2!.%9-%4!

3#).*!#.!A<B!-(!.%(8#&(-32%!0#.!8.#$8'27!(%1+.-&,!'/%!-&9%('-,)'#.(!1#$82-)&1%!#.!

*-(1#&'-&+-&,!(/-8$%&'!#0!'/%!*%9-1%!'#!'/%!-&9%('-,)'#.!)&*!'%.$-&)'-&,!'/%!-&9%('-,)'#.f(!

8).'-1-8)'-#&!-&!'/%!-&9%('-,)'-#&!?LK!"AJ!MKL:ZH?)FF:!!W#+.!8.#'#1#2!$+('!%&(+.%!'/)'!'/%!

-&9%('-,)'-#&!-(!(1-%&'-0-1)227!(#+&*!37!%&(+.-&,!1#&(-('%&17!3%'4%%&!'/%!-&*-1)'-#&!('+*-%*G!

)&*!'/%!(+3l%1'!-&12+(-#&!)&*!%Y12+(-#&!1.-'%.-)!?LK!"AJ!MKL:LE?3FF:!!U&!)22!('+*7!*%(-,&(G!7#+!

(/#+2*!%&(+.%!'/)'!-&9%('-,)'#.(!1#22%1'!'/%!)88.#8.-)'%!-&0#.$)'-#&:!!;8%1-0-1)227G!7#+!(/#+2*!

%&(+.%!'/)'!'/%!12-&-1)2!*)')!1#22%1'-#&!0#.$(!+(%*!37!'/%!-&9%('-,)'#.(!)&*!-&('-'+'-#&(!).%!

1#&(-('%&'!4-'/!'/%!12-&-1)2!8.#'#1#2:!!W#+!(/#+2*!)2(#!%&(+.%!'/)'!-&0#.$%*!1#&(%&'!

*#1+$%&'?(F!).%!1#&(-('%&'!4-'/!'/%!12-&-1)2!8.#'#1#2:!

!

F. Control Data

_)(%*!#&!#+.!2#&,!/-('#.7!-&!'/%!%9)2+)'-#&!#0!/%).'!9)29%(!)&*!'/%!%Y'%&(-9%!.%8#.'-&,!-&!'/%!

2-'%.)'+.%G!A<B!3%2-%9%(!'/)'!)!(-&,2%C).$!('+*7!4-'/!2-'%.)'+.%C3)(%*!1#&'.#2(!-(!'/%!2%)('!

3+.*%&(#$%!)88.#)1/!'#!12-&-1)2!%9)2+)'-#&!#0!)!.%82)1%$%&'!/%).'!9)29%:!!W#+.!12-&-1)2!('+*7!

(/#+2*!-&12+*%!)88.#8.-)'%!1#&'.#2(!-&12+*-&,!2-'%.)'+.%C3)(%*!#3l%1'-9%!8%.0#.$)&1%!1.-'%.-)!

?R["(F!0#.!()0%'7!*)')G!)&*!2-'%.)'+.%!).'-12%(!)&*!.%8#.'(!0#.!3#'/!()0%'7!)&*!%00%1'-9%&%((!

*)'):!!\/%!R["(!(/#+2*!3%!%(')32-(/%*!0.#$!*)')!,%&%.)'%*!0#.!)!(-$-2).!'78%!#0!.%82)1%$%&'!

/%).'!9)29%G!)&*!'/%!).'-12%(!)&*!.%8#.'(!(/#+2*!)**.%((!)!(-$-2).!'78%!#0!.%82)1%$%&'!/%).'!

9)29%!-&!'/%!()$%!9)29%!8#(-'-#&:!!\/%!1#&'.#2!*)')!0.#$!2-'%.)'+.%!).'-12%(!)&*!.%8#.'(!(/#+2*!

3%!1#22%1'%*!0.#$!('+*-%(!8+32-(/%*!-&!8%%.C.%9-%4%*!l#+.&)2(!*+.-&,!'/%!8)('!E!7%).(:!!\/%!

2-'%.)'+.%!1#&'.#2!()0%'7!*)')!(/#+2*!-&12+*%!%).27!)*9%.(%!%9%&'!.)'%!*)')G!2-&%).-g%*!2)'%!

)*9%.(%!%9%&'!.)'%!*)')G!)&*!)1'+).-)2!?+(+)227!])82)&C>%-%.F!)*9%.(%!%9%&'!.)'%!*)'):!!\/%!

2-'%.)'+.%!1#&'.#2!%00%1'-9%&%((!*)')!(/#+2*!-&12+*%!^%4!W#.=!@%).'!B((#1-)'-#&!?^W@BF!

0+&1'-#&)2!12)((-0-1)'-#&12!*)')!)&*!/%$#*7&)$-1!*)'):!!;%%!)2(#!(%1'-#&!I. Follow-Up Data

3%2#4 0#.!.%1#$$%&*)'-#&(!#&!/%$#*7&)$-1!('+*-%(!*)'):!

!

!KL!\/%!".-'%.-)!"#$$-''%%!#0!'/%!^%4!W#.=!@%).'!B((#1-)'-#&:!^#$%&12)'+.%!)&*!".-'%.-)!0#.!

<-),&#(-(!#0!<-(%)(%(!#0!'/%!@%).'!)&*!V.%)'!Q%((%2(:!5'/!%*:!_#('#&G!>)((N!I-''2%G!_.#4&!p!"#k!

K55ZNLEDCLEH:!

! K5


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

A#.!-&0)&'(!)&*!7#+&,!1/-2*.%&!.%1%-9-&,!.%82)1%$%&'!9)29%(!#.!9)29%*!1#&*+-'(!?(+1/!)(!

8+2$#&-1!9)29%*!1#&*+-'(F!-&!12-&-1)2!('+*-%(G!^W@B!0+&1'-#&)2!12)((-0-1)'-#&!*)')!).%!&#'!

)88.#8.-)'%:!!R3')-&-&,!^W@B!0+&1'-#&)2!12)((-0-1)'-#&!*)')!#&!-&0)&'(!)&*!7#+&,!1/-2*.%&!-(!

,%&%.)227!&#'!0%)(-32%!3%1)+(%!'/%(%!(+3l%1'(!).%!'##!7#+&,!'#!8.#9-*%!'/%!(7$8'#$!

-&0#.$)'-#&!&%1%(().7!0#.!(+1/!12)((-0-1)'-#&:!!A#.!'/%(%!(+3l%1'(!'/%!%9)2+)'-#&!#0!

%00%1'-9%&%((!-(!'78-1)227!3)(%*!(#2%27!#&!'/%!/%$#*7&)$-1!*)')G!4/-1/!$)7!3%!9).-#+(27!

(+882%$%&'%*!4-'/!#'/%.!%00%1'-9%&%((!*)')!(+1/!)(!1).*-)1!-$),-&,!*)')!)&*!%Y%.1-(%!'%('-&,!

*)'):!!!!

!

A<B!.%1#$$%&*(!'/%!+(%!#0!'/%!R["(!)(!2-('%*!-&!\)32%!J:K!#0!U;R!EMZ6NL66E!B&&%Y!J!

(-&1%!'/%(%!R["(!).%!3)(%*!#&!)&!%Y'%&(-9%!2-'%.)'+.%C3)(%*!.%9-%4!#0!$)&7!).'-12%(!0.#$!

*-00%.%&'!-&('-'+'-#&(:!!c%!*#!&#'!.%1#$$%&*!'/%!+(%!#0!'/%!R["(!-&!\)32%!J:L!#0!B&&%Y!J!

(-&1%!'/%(%!2)''%.!R["(!).%!3)(%*!#&!#&27!#&%!(%.-%(!#0!(+3l%1'(!?)23%-'!)!2).,%!(%.-%(F!)'!#&%!

-&('-'+'-#&:!!@#4%9%.G!-0!7#+!4-(/!'#!-&12+*%!)!1#&1+..%&'!1#&'.#2!,.#+8!-&!7#+.!('+*7G!4%!

.%1#$$%&*!'/)'!7#+!1#&')1'!'/%!<-9-(-#&!#0!").*-#9)(1+2).!<%9-1%(:!!

!

G. Sample Size and Follow-Up Effect on Complication Rate !

1. Patient-Years

c%!.%1#$$%&*!'/)'!7#+!$%)(+.%!0#22#4C+8!-&!h8)'-%&'C7%).(i!-&('%)*!#0!'/%!h9)29%C

7%).(i!3%1)+(%!*#+32%!9)29%!.%82)1%$%&'!?<QJF!(+3l%1'(G!4/#(%!0#22#4C+8!-(!%Y8.%((%*!

-&!9)29%C7%).(G!).%!'78-1)227!%Y12+*%*!0.#$!'/%!$)-&!)&)27(%(!#0!()0%'7!*)')!)&*!^W@B!

0+&1'-#&)2!12)((-0-1)'-#&!*)'):!!c%!)2(#!.%1#$$%&*!'/)'!7#+!%Y12+*%!<QJ!(+3l%1'(!0.#$!

'/%!$)-&!)&)27(-(!3%1)+(%!)*9%.(%!%9%&'(!)&*!^W@B!0+&1'-#&)2!12)((-0-1)'-#&!1)&&#'!3%!

12%).27!)*l+*-1)'%*!'#!)!8).'-1+2).!9)29%!8#(-'-#&!-&!<QJ!(+3l%1'(:!!!

!

2. Duration of Follow-Up

U&!#.*%.!'#!8.#9-*%!)!12-&-1)227!(+00-1-%&'!)$#+&'!#0!*)')!#&!'/%!-&9%('-,)'-#&)2!

.%82)1%$%&'!/%).'!9)29%G!4%!.%1#$$%&*!'/)'!)22!(+3l%1'(!3%!0#22#4%*!0#.!K 7%).!#.!$#.%:!!!

!

U0!7#+.!12-&-1)2!-&9%('-,)'-#&!-(!0#.!#&%!9)29%!8#(-'-#&G!4%!.%1#$$%&*!'/)'!7#+!0#22#4!

D66!#.!$#.%!(+3l%1'(!0#.!K!7%).!#.!$#.% 0#.!)!'#')2!#0!M66!8)'-%&'C7%).(!#0!0#22#4C+8:KD!

!

U0!'/%!('+*7!-(!0#.!'4#!9)29%!8#(-'-#&(!?-:%:G!)#.'-1!)&*!$-'.)2FG!4%!.%1#$$%&*!'/)'!7#+!

0#22#4!KE6!(+3l%1'(!0#.!#&%!7%).!#.!$#.% 0#.!%)1/!9)29%!8#(-'-#&!0#.!)!'#')2!#0!Z66!8)'-%&'C

7%).(!#0!0#22#4C+8!8%.!9)29%!8#(-'-#&:!

!KD!\/%!.%1#$$%&*%*!0#22#4C+8!#0!M66!8)'-%&'C7%).(!-(!(')'-('-1)227!*%.-9%*!)(!0#22#4(N!!;-&,2%!

()$82%!#&%C(-*%*!/78#'/%(-(!'%('-&,!1)&!3%!+(%*!'#!*%$#&('.)'%!'/)'!%)1/!#0!'/%!1#$82-1)'-#&!

.)'%(!)((#1-)'%*!4-'/!'/%!-&9%('-,)'-#&)2!*%9-1%!-(!2%((!'/)&!L!'-$%(!'/%!R["!0#.!'/)'!

1#$82-1)'-#&:!!\/%!)88.#8.-)'%!&+22!/78#'/%(-(!-(!'/)'!'/%!'.+%!.)'%!)((#1-)'%*!4-'/!'/%!

-&9%('-,)'-#&)2!*%9-1%!-(!L!#.!$#.%!'-$%(!-'(!R[":!!\#!.%l%1'!'/-(!&+22!/78#'/%(-(!-(!'#!)11%8'!'/%!

)2'%.&)'-9%!/78#'/%(-(!'/)'!'/%!'.+%!.)'%!)((#1-)'%*!4-'/!'/%!-&9%('-,)'-#&)2!*%9-1%!-(!2%((!'/)&!L!

'-$%(!-'(!R[":!!!

! L6

cris


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

!

c%!.%1#$$%&*!'/)'!7#+!1#&*+1'!'/%!12-&-1)2!('+*7!)'!%-,/'!#.!$#.%!8.-$).7!1%&'%.(G!4-'/!

D6!#.!$#.%!(+3l%1'(!-$82)&'%*!)'!%)1/!1%&'%.!0#.!)!#&%C8#(-'-#&!('+*7!)&*!KE!#.!$#.%!

(+3l%1'(!-$82)&'%*!)'!%)1/!1%&'%.!0#.!)!'4#C8#(-'-#&!('+*7:!!c%!3%2-%9%!'/)'!+(-&,!0%4%.!

'/)&!%-,/'!8.-$).7!1%&'%.(!1)&!-&'.#*+1%!3-)(!-&'#!'/%!('+*7:!

!

A#.!3#'/!#&%!8#(-'-#&!)&*!'4#!8#(-'-#&!('+*-%(G!4%!.%1#$$%&*!-$82)&'-&,!KE!#.!$#.%!

(+3l%1'(!0#.!%)1/!(-g%!)&*!%)1/!8#(-'-#&!0#.!)22!9)29%!(-g%(:!!U&!#'/%.!4#.*(G!-0!7#+.!('+*7!

)((%((%(!3#'/!)#.'-1!)&*!$-'.)2!.%82)1%$%&'(G!7#+.!('+*7!(/#+2*!%&.#22!KE!#.!$#.%!

(+3l%1'(!)'!'/%!)#.'-1!8#(-'-#&!)&*!)&!)**-'-#&)2!KE!#.!$#.%!(+3l%1'(!)'!'/%!$-'.)2!8#(-'-#&G!

0#.!%)1/!9)29%!(-g%:!!\/%!KE!(+3l%1'(!-$82)&'%*!8%.!(-g%!8%.!8#(-'-#&!1.-'%.-#&!-(!3)(%*!#&!

(')'-('-1)2!1)21+2)'-#&(!0#.!%1/#1).*-#,.)8/-1!%00%1'-9%!#.-0-1%!).%)!?SRBF!*)'):!!\/%(%!

1)21+2)'-#&(!(/#4!'/)'!-&!#.*%.!'#!)((+.%!)!(+00-1-%&'27!&)..#4!5Eo!1#&0-*%&1%!-&'%.9)2G!

'/%!$-&-$+$!&+$3%.!#0!(+3l%1'(!-$82)&'%*!4-'/!%)1/!9)29%!(-g%!-(!KE:!!U0!7#+!#$-'!)&7!

(-g%(G!4%!.%1#$$%&*!'/)'!7#+!%Y82)-&!/#4!'/%!*)')!7#+!1#22%1'!).%!.%8.%(%&')'-9%!#0!)22!

'/%!(-g%(!'/)'!7#+!-&'%&*!'#!$).=%':!

!

3. Complication Rates

B((+$-&,!'/%![#-((#&!*-('.-3+'-#&!)&*!'/%!'.+%!.)'%!3%-&,!%P+)2!'#!-'(!R["G!)&*!4-'/!

8.#3)3-2-'-%(!#0!\78%!U!%..#.!#0!6:6E!)&*!\78%!UU!%..#.!#0!6:L6G!'/%!)$#+&'!#0!*)')!

&%1%(().7!'#!)1/-%9%!'/%!($)22%('!R["!#0!K:Lo!8%.!8)'-%&'C7%).!?%Y12+*-&,!'/%!R["(!0#.!

9)29%!'/.#$3#(-(G!$)l#.!/%$#../),%G!)&*!$)l#.!8%.-9)29+2).!2%)=G!4/-1/!).%!)22!2%((!'/)&!

K:Lo!8%.!8)'-%&'C7%).F!-(!M66!8)'-%&'C7%).(!?)#.'-1!)&*!$-'.)2!8#(-'-#&(!1#$3-&%*F:KD!!\/%!

&+22!/78#'/%(-(!0#.!)!1#$82-1)'-#&!.)'%!1)&!3%!.%l%1'%*!)'!'/%!#&%C(-*%*!(-,&-0-1)&1%!2%9%2!

#0!6:6E!-0!'/%!+88%.!5Eo!1#&0-*%&1%!2-$-'!0#.!'/%!1#$82-1)'-#&!.)'%!-(!2%((!'/)&!L!'-$%(!'/%!

R["!0#.!'/)'!1#$82-1)'-#&:KZGKE

!

4. Complications

c%!.%1#$$%&*!'/)'!'/%!1#$82-1)'-#&!*)')!-&12+*%!/%$#../),%(!.%(+2'-&,!0.#$!)22!1)+(%(!

?)22C1)+(%!/%$#../),%F!.)'/%.!'/)&!l+('!/%$#../),%!.%2)'%*!'#!)&'-1#),+2)&'!'/%.)87!

?)&'-1#),+2)&'C.%2)'%*!/%$#../),%F:!!B**-'-#&)227G!4%!.%1#$$%&*!'/)'!'/%!1#$82-1)'-#&!

*)')!-&12+*%!)22C1)+(%!.%#8%.)'-#&G!9)29%C.%2)'%*!.%#8%.)'-#&G!%Y82)&'G!)22C1)+(%!*%)'/G!)&*!

9)29%C.%2)'%*!*%)'/:!!!

!

H. Pre-Operative Data

\/%!*-),&#('-1!8.%C#8%.)'-9%!*)')!1#22%1'%*!(/#+2*!-&12+*%!'/%!&#.$)2!.)&,%(!0#.!'/%!12-&-1)2!

2)3#.)'#.7!32##*!'%('(!'/)'!).%!%9)2+)'%*G!4-'/!'/%!&#.$)2!.)&,%(!3%-&,!*%'%.$-&%*!37!'/%!

2)3#.)'#.-%(!+(%*:!!

!

!KZ!V.+&=%$%-%.!VIG!a#/&(#&!<>G!)&*!^)0'%2!<"G!;)$82%!(-g%!.%P+-.%$%&'(!0#.!%9)2+)'-&,!/%).'!

9)29%(!4-'/!1#&(')&'!.-(=!%9%&'(:!A'B"%$,'C%&6"'-*+!DNEDCEMG!K55Z:!KE!S*$+&*(!I@G!a.G!",'%&D!V+-*%2-&%(!0#.!.%8#.'-&,!$#.3-*-'7!)&*!$#.')2-'7!)0'%.!1).*-)1!9)29+2).!

#8%.)'-#&(:!A'?71$%>'=%$#*16%+>'E8$)!KKLNT6MCTKKG!K55H:!

! LK


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

I. Follow-Up Data

S)1/!(+3l%1'!%&'%.%*!-&'#!'/%!('+*7!(/#+2*!3%!0#22#4%*!)11#.*-&,!'#!'/%!('+*7!8.#'#1#2:!!

B**-'-#&)227G!0#22#4C+8!*)')!(/#+2*!3%!1#22%1'%*!0#.!%)1/!(+3l%1'!+&'-2!'/%!%&'-.%!('+*7!-(!

'%.$-&)'%*!0#.!)22!(+3l%1'(:!!\/-(!0#22#4C+8!*)')!(/#+2*!3%!1#22%1'%*!37!#00-1%G!12-&-1G!#.!

/#(8-')2!9-(-'k!'%2%8/#&%!0#22#4C+8!(/#+2*!3%!+(%*!#&27!'#!9%.-07!*%)'/!#.!2#((!'#!0#22#4C+8:!!

B(!'/-(!0#22#4C+8!*)')!(/#+2*!3%!1#22%1'%*!+&'-2!'/%!%&'-.%!('+*7!-(!'%.$-&)'%*!0#.!)22!8)'-%&'(G!

'/%!0#22#4C+8!8%.-#*!$)7!3%!(-,&-0-1)&'27!2#&,%.!'/)&!(')'%*!-&!'/%!('+*7!8.#'#1#2!0#.!$#('!

8)'-%&'(:!!B11#.*-&,27G!7#+!$+('!.%1%-9%!-&0#.$%*!1#&(%&'!'#!(+1/!0#22#4C+8!8%.-#*!0.#$!)22!

(+3l%1'(!?LK!"AJ!E6:LE?)F?KFF:!!B&7!(+3l%1'!&#'!4-22-&,!'#!0+227!8).'-1-8)'%!-&!'/%!('+*7G!

-&12+*-&,!'/%!0#22#4C+8!8%.-#*G!(/#+2*!&#'!3%!%&'%.%*:KH!!!!!!

A#22#4C+8!*)')!(/#+2*!-&12+*%!'/%!&#.$)2!.)&,%(!0#.!'/%!12-&-1)2!2)3#.)'#.7!32##*!'%('(!

%9)2+)'%*!)11#.*-&,!'#!'/%!&#.$)2!.)&,%(!+(%*!37!'/%!2)3#.)'#.-%(!'/)'!1#&*+1'%*!'/%!'%('-&,:!!

[2)($)!0.%%!/%$#,2#3-&!-(!8.%0%.)32%!'#!(%.+$!2)1')'%!*%/7*.#,%&)(%G!/)8'#,2#3-&G!)&*!

.%'-1+2#17'%!1#+&'!0#.!'/%!%9)2+)'-#&!0#.!/%$#27(-(!3%1)+(%!4%!3%2-%9%!82)($)!0.%%!

/%$#,2#3-&!/)(!/-,/%.!12-&-1)2!(%&(-'-9-'7!0#.!'/%!*%'%1'-#&!#0!/%$#27(-(!'/)&!'/%!#'/%.!'/.%%!

2)3#.)'#.7!'%('(:!!

c%!.%1#$$%&*!'/)'!7#+!8.#9-*%!'/%!0#22#4-&,!%1/#1).*-#,.)8/-1!/%$#*7&)$-1!*)')G!

('.)'-0-%*!37!9)29%!(-g%N!!

! 8%)=!8.%((+.%!,.)*-%&'!

! $%)&!8.%((+.%!,.)*-%&'!

! %00%1'-9%!#.-0-1%!).%)!

! 9)29+2).!.%,+.,-')'-#&!

! %00%1'-9%!#.-0-1%!).%)!-&*%YKT!

! 8%.0#.$)&1%!-&*%Y!

! 1).*-)1!#+'8+'!

! 1).*-)1!-&*%Y:!

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!KH!R0'%&!8)'-%&'(!).%!0#22#4%*!37!'/%-.!8%.(#&)2!1).*-#2#,-('G!&#'!'/%!(+.,%#&k!'/%.%0#.%G!'/%!

-&9%('-,)'#.!(/#+2*!4#.=!-&!1#&l+&1'-#&!4-'/!'/%!8/7(-1-)&!.%(8#&(-32%!0#.!0#22#4-&,!'/%!8)'-%&'!

'#!%&(+.%!'/)'!'/%!-&9%('-,)'#.!1#22%1'(!'/%!)88.#8.-)'%!*)')!)'!'/%!1#..%1'!'-$%!8%.-#*(:!!\/-(!$)7!

3%!3%''%.!)11#$82-(/%*!-0!%-'/%.!'/%!-&9%('-,)'#.!#.!'/%!(8#&(#.!#3')-&(!1#&')1'!-&0#.$)'-#&!0#.!

'/%!0#22#4-&,!8/7(-1-)&G!(#!/%O(/%!1)&!3%!)*9-(%*!#0!'/%!)1'+)2!('+*7!8.#'#1#2:!KT!A#.!.%82)1%$%&'!8+2$#&-1!9)29%(!)&*!8+2$#&-1!9)29%*!1#&*+-'(G!4%!*#!&#'!.%1#$$%&*!'/)'!

7#+!1)21+2)'%!'/%!%00%1'-9%!#.-0-1%!).%)G!(-&1%!'/%!1#&%!(/)8%!#0!'/%!.-,/'!9%&'.-1+2).!#+'02#4!'.)1'!

$)=%(!%1/#1).*-#,.)8/-1!$%)(+.%$%&'!#0!'/%!.-,/'!9%&'.-1+2).!#+'02#4!'.)1'!*-)$%'%.!*-00-1+2':!!

\/-(!*-00-1+2'!$%)(+.%$%&'!2%)*(!'#!8#'%&'-)2!-&)11+.)'%!1)21+2)'-#&!#0!'/%!8+2$#&-1!9)29%!

%00%1'-9%!#.-0-1%!).%)!9-)!'/%!1#&'-&+-'7!%P+)'-#&!$%'/#*:!!;-$-2).27G!0#.!.%82)1%$%&'!8+2$#&-1!

9)29%(!)&*!8+2$#&-1!9)29%*!1#&*+-'(G!4%!*#!&#'!.%1#$$%&*!'/)'!7#+!1)21+2)'%!%00%1'-9%!#.-0-1%!

).%)!-&*%Y!)&*!8%.0#.$)&1%!-&*%Y!*)')G!4/-1/!).%!1)21+2)'%*!+(-&,!%00%1'-9%!#.-0-1%!).%)!*)'):!!

! LL


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

J. Clinical Laboratory Results in Children

"2-&-1)2!2)3#.)'#.7!1#22%1'-#&(!).%!9%.7!('.%((0+2!0#.!-&0)&'(!)&*!7#+&,!1/-2*.%&!.%1%-9-&,!

.%82)1%$%&'!9)29%(!#.!9)29%*!1#&*+-'(!?%:,:G!8+2$#&-1!9)29%*!1#&*+-'(F:!!\/%.%0#.%G!-'!$)7!3%!

)88.#8.-)'%!'#!#$-'!12-&-1)2!2)3#.)'#.7!1#22%1'-#&(!0#.!/%$#27(-(!%9)2+)'-#&!)'!/#(8-')2!

*-(1/).,%!)&*!D!$#&'/(!8#('C-$82)&'!-&!'/%(%!8#8+2)'-#&(:!!@#4%9%.G!4%!.%1#$$%&*!'/)'!

7#+!('-22!8%.0#.$!12-&-1)2!2)3#.)'#.7!1#22%1'-#&(!)'!H!$#&'/(!)&*!K!7%).!8#('C-$82)&'G!)&*!

)&&+)227!'/%.%)0'%.!)(!(8%1-0-%*!-&!7#+.!8.#'#1#2:!!A#.!-&0)&'(!)&*!7#+&,!1/-2*.%&!4/#!).%!

+&)32%!'#!/)9%!)22!#0!'/%!12-&-1)2!2)3#.)'#.7!32##*!'%('!1#22%1'-#&(!)11#.*-&,!'#!'/%!&#.$)2!

.)&,%(!+(%*!37!'/%!2)3#.)'#.-%(!'/)'!1#&*+1'%*!'/%!'%('-&,G!(8#'!+.-&%!+.#3-2-&#,%&!-(!)&!

)11%8')32%!'%('!0#.!/%$#27(-(!%9)2+)'-#&:!

!

K. Imaging Data

c%!.%1#$$%&*!'/)'!'/%!-$),-&,!*)')!4-'/-&!'/%!0#22#4C+8!*)')!-&12+*%!.%8#.'(!#0N!!

! %1/#1).*-#,.)$(!

! 1).*-)1!1)'/%'%.-g)'-#&(!

! )&7!#'/%.!1).*-#9)(1+2).!-$),-&,!8.#1%*+.%(G!-&12+*-&,!"\!)&*!>J!(1)&(!

! 1/%('!YC.)7(:!

!

L. Additional Information

U&!)11#.*)&1%!4-'/!LK!"AJ!MKZ:L6?3F?DF?9F?_FG!7#+.![>B!$+('!-&12+*%!)!(+$$).7!#0!'/%!

12-&-1)2!-&9%('-,)'-#&(G!-&12+*-&,!)*9%.(%!.%)1'-#&(!)&*!1#$82-1)'-#&(:!!c%!.%1#$$%&*!7#+.!

(+$$).7!(8%1-0-1)227!-&12+*%N!!

! 1)(%!(+$$).-%(!#0!%)1/!*%)'/!4-'/!)!*%'%.$-&)'-#&!#0!4/%'/%.!'/%!*%)'/!.%8.%(%&'(!)&!

%).27!#.!)!2)'%!*%)'/KMk!)&*!

! '/%!(+$$).7!#0!(+3l%1'(!&#'!1#$82%'-&,!('+*7!('.)'-0-%*!37!2#('C'#C0#22#4!+8G!*%)'/G!#.!

%Y82)&'F:!

!

c%!.%1#$$%&*!'/)'!7#+!)2(#!-&12+*%!'/%!0#22#4-&,!-&0#.$)'-#&G!-0!)9)-2)32%N!

! 2#1)'-#&(!#0!'/%!-&9%('-,)'-#&)2!(-'%(k!

! 1#$8).-(#&!#0!8.%#8%.)'-9%!)&*!8#('#8%.)'-9%!^W@B!0+&1'-#&)2!12)((!?8.%(%&'%*!)(!

'/%!8%.1%&'),%!#0!(+3l%1'(!-&!%)1/!12)((!)'!3)(%2-&%G!)'!%)1/!0#22#4C+8!'-$%C8#-&'G!)&*!

)(!'/%!8%.1%&'),%!#0!(+3l%1'(!)'!%)1/!0#22#4C+8!'-$%C8#-&'!4/#!-$8.#9%*G!4#.(%&%*G!

#.!*-*!&#'!1/)&,%!-&!12)((Fk!

! '/%!q8.%C-$82)&'q!%00%1'-9%!#.-0-1%!).%)!#0!'/%!.%82)1%$%&'!/%).'!9)29%k!!

!KM!A<B!1#&(-*%.(!)!*%)'/!#11+..-&,!4-'/-&!D6!*)7(!#0!-$82)&')'-#&!#.!*+.-&,!'/%!-&-'-)2!

/#(8-')2-g)'-#&G!4/-1/%9%.!'-$%!8%.-#*!-(!2#&,%.G!'#!3%!)&!%).27!*%)'/:!!A<B!1#&(-*%.(!)22!#'/%.!

*%)'/(!'#!3%!2)'%!*%)'/(:!

! LD

cris


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

! &+$3%.(!#0!-$82)&'%*!(+3l%1'(!('.)'-0-%*!37!-&9%('-,)'-#&)2!(-'%G!.%82)1%$%&'!9)29%!

8#(-'-#&!?%:,:G!)#.'-1G!$-'.)2G!#.!*#+32%!9)29%!.%82)1%$%&'FG!)&*!9)29%!(-g%k!

! &+$3%.(!#0!-$82)&'%*!(+3l%1'(!0#22#4%*!'#!K!7%).!8#('C-$82)&'!('.)'-0-%*!37!

-&9%('-,)'-#&)2!(-'%G!.%82)1%$%&'!9)29%!8#(-'-#&!?%:,:G!)#.'-1G!$-'.)2G!#.!*#+32%!9)29%!

.%82)1%$%&'FG!)&*!9)29%!(-g%k!

! 0#22#4C+8!*+.)'-#&!-&0#.$)'-#&!?'#')2!)&*!37!9)29%!8#(-'-#&FG!-&12+*-&,!$%)&!0#22#4C

+8G!(')&*).*!*%9-)'-#&!)&*!.)&,%!#0!0#22#4C+8G!)&*!1+$+2)'-9%!0#22#4C+8!-&!8)'-%&'C

7%).(k!

! 1#&0#+&*-&,!0)1'#.(!37!/)g).*!.%,.%((-#&!)&)27(-(!)882-%*!'#!-*%&'-07!.-(=!0)1'#.(!

?%:,:G!,%&*%.G!),%!)'!-$82)&'G!8.%C#8%.)'-9%!^W@B!0+&1'-#&)2!12)((-0-1)'-#&G!8.%9-#+(!

9)29%!(+.,%.7G!1#&1#$-')&'!1#.#&).7!).'%.7!378)((!(+.,%.7G!-$82)&'!8#(-'-#&G!)&*!

-$82)&'!(-g%FG!4/-1/!$-,/'!)00%1'!'/%!-&1-*%&1%!#0!.%#8%.)'-#&G!%Y82)&'G!)&*!*%)'/k!!

! 8)'-%&'!1#$82-)&1%!*)')!0#.!0#22#4C+8!9-(-'(G!^W@B!0+&1'-#&)2!12)((-0-1)'-#&!*)')G!

%1/#1).*-#,.)8/-1!*)')G!)&*!12-&-1)2!2)3#.)'#.7!.%(+2'(k !

! 2-('!#0!1#$82-1)'-#&(!37!8)'-%&'!-*%&'-0-1)'-#&!&+$3%.k!

! (+$$).7!#0!(+3l%1'!1#$82)-&'(!.%1%-9%*k!

! 1)(%!.%8#.'!0#.$(!0#.!)!K6o!.)&*#$!()$82-&,!#0!'/%!(+3l%1'!8#8+2)'-#&k !

! 1#8-%(!#0!1)(%!.%8#.'!0#.$(!0#.!)22!(+3l%1'(!&#'!1#$82%'-&,!'/%!('+*7k!

! %Y82)&'!)&)27(-(!-&!)22!1)(%(!4/%&!)!9)29%!-(!%Y82)&'%*!#.!)&!)+'#8(7!-(!8%.0#.$%*k!

)&*!

! *%)'/!.%8#.'(!-&12+*-&,!)+'#8(7!.%8#.'(G!4/%&!)9)-2)32%G!%(8%1-)227!4/%&!'/%!1)+(%!#0!

*%)'/!/)(!3%%&!12)((-0-%*!)(!&#&C9)29%!.%2)'%*:!

!

M. Database Closure

\/%!12-&-1)2!*)')!-&!7#+.![>B!)882-1)'-#&!(/#+2*!3%!1+..%&'!'#!4-'/-&!(-Y!$#&'/(!#0!'/%!*)'%!

#0!(+3$-((-#&:!!W#+!$+('!)2(#!8%.-#*-1)227!+8*)'%!7#+.!8%&*-&,!)882-1)'-#&!4-'/!&%4!()0%'7!

)&*!%00%1'-9%&%((!-&0#.$)'-#&!2%).&%*!0.#$!#&,#-&,!#.!1#$82%'%*!('+*-%(!?LK!"AJ!MKZ:L6?%FF!

!

N. Subject Compliance

;+3l%1'!1#$82-)&1%!(/#+2*!3%!1)21+2)'%*!)(!'/%!0#22#4-&,!0#+.!8%.1%&'),%(N!'/%!&+$3%.!#0!

(+3l%1'(!/)9-&,!1#$82%'%*!0#22#4C+8!9-(-'(G!4-'/!^W@B!0+&1'-#&)2!12)((-0-1)'-#&!*)')G!4-'/!

%1/#1).*-#,.)8/-1!*)')G!)&*!4-'/!12-&-1)2!2)3#.)'#.7!.%(+2'(!)'!%)1/!0#22#4C+8!'-$%C8#-&'G!

*-9-*%*!37!'/%!'#')2!&+$3%.!#0!-$82)&'%*!(+3l%1'(!)9)-2)32%!?-:%:G!4/#!/)9%!&#'!*-%*!#.!/)*!

'/%-.!9)29%!%Y82)&'%*F!)&*!%2-,-32%!?-:%:G!4/#!/)9%!.%)1/%*!'/%!,-9%&!'-$%C8#-&'F!0#.!0#22#4C+8!

)'!'/)'!8).'-1+2).!'-$%C8#-&':!!\/%!'#')2!&+$3%.!#0!(+3l%1'(!/)9-&,!%1/#1).*-#,.)8/7!%Y)$(!

(/#+2*!3%!'/%!()$%!)(!'/%!'#')2!&+$3%.!#0!(+3l%1'(!4-'/!*)')!0#.!%)1/!(8%1-0-1!

%1/#1).*-#,.)8/-1!/%$#*7&)$-1!8).)$%'%.!?-:%:G!8%)=!8.%((+.%!,.)*-%&'G!$%)&!8.%((+.%!

! LZ


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

,.)*-%&'G!%00%1'-9%!#.-0-1%!).%)G!%00%1'-9%!#.-0-1%!).%)!-&*%YGKT!8%.0#.$)&1%!-&*%YG!1).*-)1!

#+'8+'G!1).*-)1!-&*%YG!)&*!9)29+2).!.%,+.,-')'-#&F:!

!

O. Data Pooling

c%!3%2-%9%!'/)'!8##2-&,!*)')!0.#$!$#.%!'/)&!#&%!9)29%!8#(-'-#&G!(+1/!)(!8##2-&,!'/%!*)')!

0.#$!'/%!)#.'-1!)&*!$-'.)2!9)29%!8#(-'-#&(G!$)(=(!8#'%&'-)2!*-00%.%&1%(!-&!9)29%!0+&1'-#&!)&*!

9)29%C.%2)'%*!)*9%.(%!%9%&'(:!!\/%.%0#.%G!7#+!(/#+2*!('.)'-07!'/%!*)')!37!9)29%!8#(-'-#&!

-&('%)*!#0!8##2-&,!'/%(%!*)'):!

!

P. Adverse Events and Complication Rates

W#+.![>B!(/#+2*!-&12+*%!'/%!)1'+)2!&+$3%.!#0!)*9%.(%!%9%&'(:!!U&!)**-'-#&G!4%!.%1#$$%&*!

'/)'!7#+!%Y8.%((!%).27!1#$82-1)'-#&!.)'%(!)(!'/%!&+$3%.!#0!)*9%.(%!%9%&'(!*-9-*%*!37!'/%!'#')2!

&+$3%.!#0!(+3l%1'(G!)(!.%1#$$%&*%*!37!S*$+&*(!",'%&DKE!c%!.%1#$$%&*!'/)'!7#+!-&12+*%!

2-&%).-g%*!2)'%!1#$82-1)'-#&!.)'%(:!!I-&%).-g%*!2)'%!1#$82-1)'-#&!.)'%(!).%!1)21+2)'%*!)(!'/%!

&+$3%.!#0!2)'%!)*9%.(%!%9%&'(!*-9-*%*!37!'/%!'#')2!&+$3%.!#0!2)'%!8)'-%&'C7%).(:!!

!!

Q. Foreign Data

B&7!0#.%-,&!*)')!(+3$-''%*!-&!(+88#.'!#0!7#+.![>B!)882-1)'-#&!$+('!1#$827!4-'/!LK!"AJ!

MKZ:KE:!

!

U0!7#+!).%!.%27-&,!(#2%27!#&!0#.%-,&!*)')!'#!(+88#.'!7#+.![>B!)882-1)'-#&!0#.!)!.%82)1%$%&'!

/%).'!9)29%G!4%!.%1#$$%&*!7#+!8.#9-*%!'/%!+(+)2!#&%C7%).!*)')!)(!4%22!)(!+8C'#C*)'%!

-&0#.$)'-#&!-&12+*-&,!)&&+)2!0#22#4C+8!?%:,:G!^%4!W#.=!@%).'!B((#1-)'-#&!?^W@BF!/%).'!

0)-2+.%!12)((-0-1)'-#&!(1/%$%GKL!%1/#1).*-#,.)$G!)&*!32##*!'%('(!)11#.*-&,!'#!'/%!&#.$)2!

.)&,%(!+(%*!37!'/%!2)3#.)'#.-%(!'/)'!1#&*+1'%*!'/%!'%('-&,:!!W#+.!*)')!(/#+2*!*%$#&('.)'%!

2#&,C'%.$!8%.0#.$)&1%!)&*!0)-2+.%!$#*%G!)&*!-&12+*%!)+'#8(7!#.!%Y82)&'!)&)27(%(G!4/%&!

)9)-2)32%:!

XIV. PMA Supplements

B&!)88.#9%*![>B!(+882%$%&'!-(!,%&%.)227!.%P+-.%*!8.-#.!'#!$)=-&,!)!1/)&,%!)00%1'-&,!'/%!

()0%'7!#.!%00%1'-9%&%((!#0!7#+.!*%9-1%:!?LK!"AJ!MKZ:D5F:K5!!J%1#$$%&*)'-#&(!3%2#4!)**.%((!

(8%1-)2!1#&(-*%.)'-#&(!.%2)'%*!'#!$#*-0-1)'-#&(!#0!'/%!(%4-&,!.-&,!1#&0-,+.)'-#&!)&*!9)29%*!

1#&*+-'(:!

!

!

!

!

!K5!;%%!Modifications to Devices Subject to Premarket Approval (PMA) - The PMA

Supplement Decision-Making ProcessG!

/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$6

M5LTZ:/'$:!

! LE




-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

A. Modifications to the Sewing Ring Configuration

V%&%.)227G!12-&-1)2!*)')!$)7!&#'!3%!&%%*%*!'#!%(')32-(/!'/%!()0%'7!)&*!%00%1'-9%&%((!#0!

)2'%.&)'%!(%4-&,!.-&,!1#&0-,+.)'-#&(!8.#9-*%*!7#+!/)9%!&#'!)2'%.%*!'/%!(+3('.+1'+.%(!#0!'/%!

9)29%:!!c%!.%1#$$%&*!'/)'!7#+!9)2-*)'%!1/)&,%(!'#!7#+.!(%4-&,!.-&,!1#&0-,+.)'-#&!37!

1#&*+1'-&,!*5'6*,$1!('+*-%(!'#!12%).27!%(')32-(/!'/)'!'/%!&%4!(%4-&,!.-&,!1)&!(+88#.'!'/%!

8/7(-#2#,-1)2!2#)*-&,:!!c%!.%1#$$%&*!'/)'!7#+!1#$8).%!'/%!(8%1-0-1!$)'%.-)2!?$)&+0)1'+.%.G!

4%)9%G!%'1:F!4-'/!'/%!$)'%.-)2!+(%*!-&!7#+.!)88.#9%*![>B:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!

9)2-*)'%!1#$$#&G!12-&-1)227C)11%8'%*!(%4-&,!.-&,!$)'%.-)2(!?8#27'%'.)02+#.#%'/72%&%!r[\ASsG!

8#27%'/72%&%!'%.%8/'/)2)'%!r[S\sF!4-'/!)&-$)2!/%)2-&,!*)')!(+882%$%&'%*!4-'/!%Y82)&'!*)'):!!

A#.!)&7!(%4-&,!.-&,!$)'%.-)2(!#'/%.!'/)&![\AS!)&*![S\G!/#4%9%.G!4%!.%1#$$%&*!'/)'!7#+!

9)2-*)'%!'/%!$#*-0-1)'-#&!4-'/!12-&-1)2!*)'):!

!

B. Valved Conduits

c%!.%1#$$%&*!'/)'!7#+!1#&*+1'!12-&-1)2!-&9%('-,)'-#&(!0#.!.%82)1%$%&'!9)29%*!1#&*+-'(:!!

"2-&-1)2!-&9%('-,)'-#&(!$)7!&#'!3%!&%%*%*!4/%&!3#'/!'/%!9)29%!)&*!'/%!1#&*+-'!#.!,.)0'!).%!

2%,)227!$).=%'%*:!!U0!3#'/!).%!2%,)227!$).=%'%*G!*5'6*,$1!-&9%('-,)'-#&(!$)7!3%!(+00-1-%&':!!

c/%'/%.!)&!*5'6*,$1!-&9%('-,)'-#&!-(!)88.#8.-)'%!*%8%&*(!#&!7#+.!.-(=!)((%(($%&'k!%:,:G!'/%!

.-(=!)((%(($%&'!0#.!)!$#*-0-%*!*%(-,&!$)7!-&*-1)'%!'/%!)3-2-'7!#0!'/%!9)29%O,.)0'!-&'%.0)1%!'#!

4-'/(')&*!8/7(-#2#,-1)2!2#)*-&,!-(!8#'%&'-)227!*-00%.%&':!!U&!'/-(!1)(%G!*5'6*,$1!('+*-%(!$)7!3%!

)88.#8.-)'%!'#!9)2-*)'%!)!1/)&,%!-&!'/%!*%(-,&!#0!'/%!9)29%O,.)0'!-&'%.0)1%:!!R.G!0#.!-&(')&1%G!-0!

7#+!$#*-07!7#+.!*%9-1%!37!+(-&,!)!1#)'%*!,.)0'G!'/%!.-(=!)((%(($%&'!(/#+2*!)**.%((!4/%'/%.!

'/%.%!).%!)&7!8#'%&'-)2!)*9%.(%!%00%1'(!'#!'/%!1#)'-&,!?%:,:G!2#((!#0!1#)'-&,!-&'%,.-'7!2%)*-&,!'#!

32%%*-&,!*+%!'#!'/%!$)&+0)1'+.-&,!('%8(!)((#1-)'%*!4-'/!(%4-&,!'/%!9)29%!-&'#!'/%!,.)0'F:!

!

XV. Professional Labeling

I)3%2-&,!.%P+-.%$%&'(!0#.!$%*-1)2!*%9-1%(!).%!*%(1.-3%*!-&!LK!"AJ![).'!M6K:L6!!U&!)11#.*)&1%!

4-'/!LK!"AJ!MKZ:L6?3F?K6FG!7#+!$+('!(+3$-'!)22!8.#8#(%*!2)3%2-&,!-&!7#+.![>B:!!c%!

.%1#$$%&*!'/)'!7#+.!2)3%2-&,!-&12+*%!'/%!-&0#.$)'-#&!0#+&*!-&!;%1'-#&!H:L:D!)&*!B&&%Y!d!#0!

U;R!EMZ6NL66E!#.!%P+-9)2%&'!(+,,%('%*!0#.!-&12+(-#&!-&!2)3%2-&,!)&*!-&('.+1'-#&(!0#.!+(%. U&!

)**-'-#&G!7#+.!2)3%2-&,!(/#+2*!-&12+*%!'/%!-&0#.$)'-#&!*%(1.-3%*!3%2#4:!

!

A. Non-Sterile Devices!

U0!7#+!-&'%&*!'#!$).=%'!7#+.!*%9-1%!-&!&#&C('%.-2%!0#.$G!7#+!(/#+2*!8.#9-*%!12%).!)&*!

)*%P+)'%!-&('.+1'-#&(!0#.!('%.-2-g)'-#&!-&!7#+.!-&('.+1'-#&(!0#.!+(%!4-'/!)11%8')32%!8).)$%'%.(!

'#!3%!+(%*G!(+1/!)(!'%$8%.)'+.%G!8.%((+.%G!*4%22!'-$%(G!)&*!4/%'/%.!#.!&#'!.%C('%.-2-g)'-#&!

+(-&,!'/%(%!8).)$%'%.(!-(!)88.#8.-)'%G!!c%!)2(#!.%1#$$%&*!'/)'!7#+!8.#$-&%&'27!-&*-1)'%!-&!

7#+.!8)1=),%!2)3%2-&,!)&*!-&('.+1'-#&(!0#.!+(%!'/)'!7#+.!*%9-1%!-(!8.#9-*%*!&#&C('%.-2%:!

!L6!;%%!CDRH!Device Advice!)9)-2)32%!)'!

/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OR9%.9-%4O<%9-1%I)3%2-&,O

*%0)+2':/'$!0#.!)**-'-#&)2!-&0#.$)'-#&!)3#+'!*%9-1%!2)3%2-&,!.%P+-.%$%&'(:!

! LH

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/DeviceLabeling/default.htm

http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/DeviceLabeling/default.htm


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

!

B. Resterilization

U0!'/%!*%9-1%!1)&!3%!.%('%.-2-g%*G!'/%&!'/%!2)3%2-&,!(/#+2*!-&12+*%!'/%!.%1#$$%&*%*!

('%.-2-g)'-#&!$%'/#*!)&*!8).)$%'%.(!'#!+(%:!

!

C. Magnetic Resonance Imaging (MRI)

A#.!-&0#.$)'-#&!.%,).*-&,!>),&%'-1!J%(#&)&1%!?>JF!()0%'7!'%('-&,G!82%)(%!(%%!A<B!

,+-*)&1%!*#1+$%&'!%&'-'2%*G!hS(')32-(/-&,!;)0%'7!)&*!"#$8)'-3-2-'7!#0![)((-9%!U$82)&'(!-&!

'/%!>),&%'-1!J%(#&)&1%!?>JF!S&9-.#&$%&':iLK!

XVI. Patient Labeling

U0!7#+!8.#8#(%!'#!8.#9-*%!8)'-%&'!2)3%2-&,G!%:,:G!!)!8)'-%&'!$)&+)2!#.!8)'-%&'!-*%&'-0-1)'-#&!1).*(!

4-'/!7#+.!*%9-1%G!7#+!$+('!(+3$-'!'/%!8.#8#(%*!2)3%2-&,!-&!)11#.*)&1%!4-'/!LK!"AJ!

MKZ:L6?3F?K6F:!!\/%!8)'-%&'!$)&+)2!(/#+2*!-&12+*%!)!*-(1+((-#&!#0!)&'-1#),+2)'-#&!'/%.)87!)&*!

'/%!-$8#.')&1%!#0!0#22#4C+8!9-(-'(:!!;%%!Guidance on Medical Device Patient LabelingLL!0#.!

$#.%!-&0#.$)'-#&!)3#+'!'/%!1#&'%&'(!#0!8)'-%&'!2)3%2-&,:!

\/%!8)'-%&'!-*%&'-0-1)'-#&!1).*!(/#+2*!(/#4!'/%!0#22#4-&,N!

! 8)'-%&'!&)$%!

! *)'%!#0!-$82)&'!

! &)$%!)&*!1#&')1'!-&0#.$)'-#&!0#.!'/%!-$82)&'-&,!8/7(-1-)&G!'/%!0#22#4-&,!8/7(-1-)&G!)&*!'/%!*%9-1%!$)&+0)1'+.%.!

! %$%.,%&17!1#&')1'!8%.(#&!

! *%9-1%!&)$%G!(-g%G!8#(-'-#&!)&*!(%.-)2!&+$3%.!

! )&7!$%*-1)'-#&(!)&*!*#(),%(!

! >J!;)0%!#.!>J!"#&*-'-#&)2!-&0#.$)'-#&LD:!

!LK!!\/-(!,+-*)&1%!*#1+$%&'!1)&!3%!#3')-&%*!)'N!

/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$K

6TT6E:/'$!0#.!,+-*)&1%!#&!>J!()0%'7!'%('-&,!#0!7#+.!*%9-1%:!!!!!!LL!\/-(!,+-*)&1%!*#1+$%&'!1)&!3%!#3')-&%*!)'N!

/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$6

T6TML:/'$:! !LD!!A#.!)**-'-#&)2!-&0#.$)'-#&G!82%)(%!(%%G!hS(')32-(/-&,!;)0%'7!)&*!"#$8)'-3-2-'7!#0![)((-9%!

U$82)&'(!-&!'/%!>),&%'-1!J%(#&)&1%!?>JF!S&9-.#&$%&'i!)'!

/''8NOO444:0*):,#9O>%*-1)2<%9-1%(O<%9-1%J%,+2)'-#&)&*V+-*)&1%OV+-*)&1%<#1+$%&'(O+1$K

6TT6E:/'$:!

! LT








-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

Appendix A. Shelf Life Validation

W#+.![>B!)882-1)'-#&!$+('!-&12+*%!)!'%1/&-1)2!(%1'-#&!4/-1/!(/)22!1#&')-&!*)')!)&*!

-&0#.$)'-#&G!-&12+*-&,!'/%!.%(+2'(!#0!'/%!(/%20!2-0%!'%('-&,G!-&!(+00-1-%&'!*%')-2!'#!8%.$-'!A<B!'#!

*%'%.$-&%!4/%'/%.!'#!)88.#9%!#.!*%&7!7#+.!)882-1)'-#&!?LK!"AJ!MKZ:L6?3F?HF?-FF:!!W#+!(/#+2*!

9)2-*)'%!7#+.!.%82)1%$%&'!/%).'!9)29%!)&*!8)1=),%!#9%.!'/%!(/%20!2-0%!#0!'/%!*%9-1%!3%1)+(%!#0!'/%!

8#'%&'-)2!0#.!9)29%!*%'%.-#.)'-#&!'/)'!-(!&#'!.%)*-27!9-(-32%!'#!'/%!(+.,%#&G!3+'!'/)'!1#+2*!

(+3(%P+%&'27!$)&-0%('!-&!'/%!8)'-%&'!)(!8.%$)'+.%!9)29%!0)-2+.%:!!A#.!)22!9)29%(G!4%!.%1#$$%&*!

'/)'!7#+!1#&*+1'!1#$8).)'-9%!8%.0#.$)&1%!'%('-&,!#0!),%*!)&*!+&),%*!4/#2%!9)29%(G!)(!

*%(1.-3%*!3%2#4:!

!

c%!.%1#,&-g%!'/)'!(#$%!(/%20!2-0%!9)2-*)'-#&!'%('(!-*%&'-0-%*!-&!'/-(!,+-*)&1%!).%!)882-1)32%!'#!

#&27!1%.')-&!9)29%(:!!U0!7#+!3%2-%9%!'/)'!)!8).'-1+2).!'%('!*#%(!&#'!)8827!'#!7#+.!*%9-1%G!4%!

.%1#$$%&*!'/)'!7#+!8.#9-*%!7#+.!.)'-#&)2%!0#.!#$-''-&,!'/%!'%(':!!!

!

A#.!(/%20!2-0%!9)2-*)'-#&G!4%!.%1#$$%&*!'/)'!7#+!%Y82)-&!/#4!%)1/!#0!'/%!0#22#4-&,!-(!12-&-1)227!

.%8.%(%&')'-9%!)&*!-&!),.%%$%&'!4-'/!'/%!#8%.)'-#&)2!(8%1-0-1)'-#&(!#0!'/%!*%9-1%N!

! '%('!8).)$%'%.(!?(7('%$-1!8.%((+.%G!3%)'!.)'%G!('.#=%!9#2+$%G!1).*-)1!#+'8+'!?"RFG!'-((+%!

1#$82-)&1%G!%'1:F!

! '%('!*+.)'-#&!!

! )882-1)32%!8%.0#.$)&1%!(8%1-0-1)'-#&:!

!

A. Test Valve Selection!!!

\#!%(')32-(/!)!(/%20!2-0%!0#.!7#+.!*%9-1%G!7#+!(/#+2*!%9)2+)'%!4/#2%!9)29%(!),%*!'#!'/%!2)3%2%*!

(/%20!2-0%!)&*!+&),%*!4/#2%!9)29%(!-&!)!(-*%!37!(-*%!$)&&%.!-&!#.*%.!'#!$)=%!)!1#$8).-(#&:!!

c%!.%1#$$%&*!'/)'!7#+!%9)2+)'%N!

! 9)29%(!#0!'/%!($)22%('G!-&'%.$%*-)'%G!)&*!2).,%('!(-g%(!

! 9)29%(!('%.-2-g%*!'#!'/%!$)Y-$+$!&+$3%.!#0!1712%(!-&!)11#.*)&1%!4-'/!'/%!%(')32-(/%*!

)&*!9)2-*)'%*!('%.-2-g)'-#&!8.#1%((!

! 0-&)2!0-&-(/%*!8.#*+1'!?-:%:G!(+3l%1'%*!'#!)22!$)&+0)1'+.-&,!8.#1%((%(G!-&12+*-&,!)&!

)&'-C1)21-0-1)'-#&!'.%)'$%&'G!-0!)882-1)32%F!

! 9)29%(!(+3l%1'%*!'#!(-$+2)'%*!*-('.-3+'-#&!)&*!/)&*2-&,!1#&*-'-#&(:!

!

B. Real-Time and Accelerated Aging

c%!,%&%.)227!.%1#$$%&*!.%)2C'-$%!),-&,!#0!'%('!9)29%(:!!@#4%9%.G!-0!7#+!+(%!)11%2%.)'%*!

),-&,!'%1/&-P+%(G!4%!.%1#$$%&*!'/)'!7#+!*%(1.-3%!/#4!7#+!9)2-*)'%*!7#+.!)11%2%.)'%*!),-&,!

$%'/#*(!)&*!8.#9-*%!'/%!.%(+2'(!#0!)&7!9)2-*)'-#&!('+*-%(!1#&*+1'%*:!!c%!.%1#$$%&*!),-&,!

#0!'/%!4/#2%!9)29%G!-&12+*-&,!'/%!('%&'!0#.!'/#(%!9)29%(!4-'/!('%&'(G!3%1)+(%!'/%!('#.),%!

(#2+'-#&!1)&!/)9%!)&!-$8)1'!#&!'/%!-&'%,.-'7!#0!'/%!('%&':!!@#4%9%.G!'/%!('%&'!$)7!3%!.%$#9%*!

0#.!'%('-&,:!!B,-&,!('+*-%(G!4/%'/%.!.%)2C'-$%!#.!)11%2%.)'%*G!(/#+2*!)**.%((!'/%!%00%1'(!#0N!

! '%$8%.)'+.%!

! LM

cris


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

! /+$-*-'7!

! 8.%((+.%!

! 2-,/'!%Y8#(+.%!

! (/-88-&,!)&*!/)&*2-&,:!!!

!

C. Device Stability

c%!.%1#$$%&*!'/)'!7#+!%9)2+)'%!'/%!0+&1'-#&)2!8%.0#.$)&1%G!('.+1'+.)2!-&'%,.-'7G!'-((+%!

$#.8/#2#,7G!-0!)882-1)32%G!)&*!8.#8%.'-%(!#0!'/%!*%9-1%!)'!g%.#!'-$%!)&*!)'!'/%!2)3%2%*!(/%20!

2-0%:!!c%!.%1#$$%&*!'/)'!7#+!%Y82)-&!7#+.!.)'-#&)2%!0#.!%)1/!'%('!$%'/#*!+(%*:!

!

1. Hydrodynamic Performance

\#!*%$#&('.)'%!/7*.#*7&)$-1!8%.0#.$)&1%G!4%!.%1#$$%&*!1#$8).-&,!*)')!0.#$!'/%!

0#22#4-&,!'%('(!#&!),%*!)&*!+&),%*!*%9-1%(N

! ('%)*7!0#.4).*!02#4!?"[G!SRBF!!

! 8+2()'-2%!0#.4).*!02#4!?"[G!SRBF!!

! 8+2()'-2%!.%,+.,-')'-#&!!

! )&'-C1)21-0-1)'-#&!%00%1'(G!-0!)882-1)32%G!?)(!*%'%.$-&%*!37!(+31+')&%#+(!

-$82)&')'-#&!-&!.)'(!#.!.)33-'(F:!

!

2. Structural Integrity

\#!*%$#&('.)'%!('.+1'+.)2!-&'%,.-'7G!4%!.%1#$$%&*!1#$8).-&,!*)')!0.#$!'/%!0#22#4-&,!

'%('(G!-0!)882-1)32%G!#&!),%*!)&*!+&),%*!*%9-1%(N!!

! 2%)02%'!*+.)3-2-'7!

! 2%)02%'!8.#2)8(%!?)(!*%'%.$-&%*!37!('%)*7!3)1=02#4!'%('-&,F:!

! (%4-&,!1+00!-&'%,.-'7!?8+22!'%('-&,F!

! (%4-&,!.-&,!-&'%,.-'7!?8+22!'%('-&,F!

! ('%&'!0)'-,+%!

! ('%&'!1.%%8!

! (1)&&-&,!%2%1'.#&!$-1.#(1#87!?;S>F!)&)27(%(!

! 8#27$%.-1!('%&'!1/%$-1)2!1#&1%&'.)'-#&!)&)27(%(:!

!

3. Tissue Morphology and Properties

\#!*%$#&('.)'%!'/)'!'/%!(/%20!2-0%!('#.),%!*#%(!&#'!)*9%.(%27!)00%1'!'-((+%!$#.8/#2#,7!)&*!

8.#8%.'-%(G!-0!)882-1)32%, 4%!.%1#$$%&*!1#$8).-&,!*)')!0.#$!'/%!0#22#4-&,!'%('(!#&!),%*!

)&*!+&),%*!*%9-1%(N!!

! /-('#2#,7!4-'/!(')-&-&,!

! L5

cris

cris


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

! 0-Y)'-#&!(')3-2-'7!?9-)!(/.-&=),%!'%$8%.)'+.%!#.!*-00%.%&'-)2!(1)&&-&,!1)2#.-$%'.7F!

! .%(-*+)2(!-&!('#.),%!(#2+'-#&!?%:,:G!)2*%/7*%!88$F!

! 3-#$%1/)&-1)2!8.#8%.'-%(!?3-)Y-)2!'%('-&,G!1.%%8!'%('-&,F:!

!

4. Storage Solution

c%!.%1#$$%&*!'/)'!7#+!)((%((!'/%!('#.),%!(#2+'-#&!)(!8).'!#0!'/%!(/%20!2-0%!9)2-*)'-#&:!!

"/)&,%(!-&!8@G!1/%$-1)2!1#$8#(-'-#&G!8#27$%.-g)'-#&!#.!3.%)=*#4&G!)(!4%22!)(!2%)=),%!

$)7!#11+.!)&*!(/#+2*!3%!%9)2+)'%*:!![.#2#&,%*!*%,.)*)'-#&!#0!'/%!('#.),%!(#2+'-#&!$)7!

/)9%!)&!%00%1'!#&!'-((+%!P+)2-'7:!!W#+.!)((%(($%&'!#0!'/%!('#.),%!(#2+'-#&!(/#+2*!-&12+*%!

)&!)&)27(-(!#0!'/%!.%(-*+)2(!-&!'/%!('#.),%!(#2+'-#&!)&*!)&)27(-(!#0!8)1=),%!1#$8#&%&'(!

2%)1/%*!-&'#!'/%!('#.),%!(#2+'-#&!)'!'/%!2)3%2%*!(/%20!2-0%!#0!'/%!*%9-1%:!!!

!

5. Package Integrity

W#+!$+('!%&(+.%!'/)'!*%9-1%!8)1=),%(!).%!*%(-,&%*!)&*!1#&('.+1'%*!'#!8.#'%1'!'/%!*%9-1%!

0.#$!)2'%.)'-#&!#.!*)$),%!*+.-&,!'/%!1+('#$).7!1#&*-'-#&(!#0!8.#1%((-&,G!('#.),%G!

/)&*2-&,G!)&*!*-('.-3+'-#&!?LK!"AJ!ML6:KD6F:!!c%!.%1#$$%&*!'/)'!7#+!%9)2+)'%!'/%!

8)1=),%!-&'%,.-'7!#0!'/%!8.#*+1'!8)1=),-&,!)'!g%.#!'-$%!)&*!)'!'/%!2)3%2%*!(/%20!2-0%G!

8.%0%.)327!+(-&,!)!$%'/#*!'/)'!%9)2+)'%(!'/%!4/#2%!8)1=),%!.)'/%.!'/)&!#&27!'/%!(%)2!).%):!!

\/%!8)1=),%!(/#+2*!1#&')-&!%-'/%.!'/%!.%)2!8.#*+1'G!#.!)!(-$+2)'%*!8.#*+1'!'/)'!/)(!

(-$-2).!$)((!)&*!,%#$%'.7:!!W#+!(/#+2*!-&12+*%!7#+.!.)'-#&)2%!0#.!'/%!'%('!$%'/#*(!

%$82#7%*:!

!

!

!

Shelf Life Validation Information – Tabular Format Example

SAMPLE PREPARATION PLANNED QUALIFICATION

& VALIDATION STUDIES

SAMPLE SIZE

[subject (control)] Sterilization Aging Distribution & Handling

Other (e.g., treatments)

ACCEPTANCE CRITERIA

Valve in vitro hydrodynamic performance:

Steady forward flow ("P, EOA)

Pulsatile forward flow

("P, EOA)

Pulsatile regurgitation

Anti-calcification effect (if applicable) determined by subcutaneous implantation in rats or rabbits

Valve structural integrity:

Leaflet durability

Leaflet prolapse determined by steady backflow testing

! D6


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!Sewing cuff integrity (pull testing)

Sewing ring integrity (pull testing)

Stent fatigue

Stent creep

Stent SEM analyses

Polymeric stent chemical concentration analyses

Valve tissue morphology & properties:

Histology (with staining)

Fixation stability (shrink temperature or differential scanning!calorimetry)

Residuals in storage solution (e.g., aldehyde ppm)

Biomechanical properties (biaxial testing, creep, and corrosion)

Storage solution:

Volume

Chemical composition

pH

Leaching analysis (of package components into storage solution, particularly if EtO sterilized)

Package integrity:

Test method used

Real or simulated product

!

! DK


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!

Appendix B. Cavitation Testing for Rigid Heart Valves

")9-')'-#&!%.#(-#&!?)&*!-&!(#$%!1)(%(G!1)')('.#8/-1!('.+1'+.%!0)-2+.%F!/)(!#11+..%*!-&!(#$%!.-,-*!

.%82)1%$%&'!/%).'!9)29%!*%(-,&(:!!B**-'-#&)227G!1)9-')'-#&!1)&!3%!-&*+1%*!-&!$#('!.-,-*!/%).'!

9)29%(!*5'6*,$1D!!\/+(G!4%!.%1#$$%&*!1)9-')'-#&!8#'%&'-)2!'%('-&,!0#.!.-,-*!9)29%(:!!;-&1%!&#!#&%!

'%('!-(!(+00-1-%&'!'#!)((%((!'/%!1)9-')'-#&!8#'%&'-)2!#0!)!&%4!.-,-*!.%82)1%$%&'!9)29%!*%(-,&G!4%!

.%1#$$%&*!'/)'!7#+!8%.0#.$!)!8.%12-&-1)2!*5'6*61!('+*7G!(-$+2)'%*!2#&,!'%.$!*5'6*,$1!('+*7!?-:%:G!

*+.)3-2-'7!'%('-&,F!'#!)((%((!8#((-32%!1)9-')'-#&!*)$),%G!)&*!%Y)$-&%!'/%!)&-$)2!('+*7!)&*!

12-&-1)2!?-0!)882-1)32%F!%Y82)&'%*!9)29%(!0#.!%9-*%&1%!#0!1)9-')'-#&:!!!

!

\/-(!)88%&*-Y!.%8.%(%&'(!#+.!+&*%.(')&*-&,!#0!*5'6*,$1'1)9-')'-#&!'%('!$%'/#*(!)'!'/%!'-$%!'/-(!

,+-*)&1%!4)(!-((+%*:!!W#+!(/#+2*!.%9-%4!(')'%!#0!'/%!).'!1)9-')'-#&!'%('-&,!3%0#.%!-$82%$%&'-&,!)!

8.#'#1#2:!!R+.!,%&%.)2!.%1#$$%&*)'-#&(!0#.!'%('!8).)$%'%.(!).%!,-9%&!3%2#4:!!!

!

A. Test Valve Selection!!!

c%!.%1#$$%&*!'/)'!7#+!'%('!'4#!#0!'/%!($)22%('!)&*!'4#!#0!'/%!2).,%('!9)29%!(-g%(:!

!

B. Test Valve Mounting!!!

A#.!1)9-')'-#&!'%('-&,G!'/%!9)29%(!(/#+2*!3%!.-,-*27!$#+&'%*!-&!'/%!$-'.)2!8#(-'-#&!#0!)!/%).'!

(-$+2)'#.:!!U0!&#!$-'.)2!9)29%!$#*%2!-(!+&*%.!%9)2+)'-#&G!)!'%('!8.#'#1#2!0#.!'/%!)#.'-1!8#(-'-#&!

(/#+2*!3%!*%9%2#8%*:!

!

C. Reference Valves!!!

c%!.%1#$$%&*!'/)'!7#+!+(%!'4#!()$82%(!#0!)&!A<BC)88.#9%*!9)29%!)(!.%0%.%&1%!9)29%(:!

!

D. Working Fluid!!!

\/%!4#.=-&,!02+-*!(/#+2*!3%!8/7(-#2#,-1)2!()2-&%!)22#4%*!'#!1#$%!'#!%P+-2-3.-+$!4-'/!.##$!

)'$#(8/%.%!0#.!LZ!/#+.(:!

!

E. Atrial Chamber!!!

\/%!)'.-)2!1/)$3%.!(/#+2*!3%!#8%&G!4-'/!)!1.#((!(%1'-#&)2!).%)!,.%)'%.!'/)&!TE!1$L:!

!

F. Atrial Pressure!!!

\/%!$%)&!)'.-)2!8.%((+.%!#&!'/%!'%('!9)29%!(/#+2*!3%!2%((!'/)&!T!$$@,:!

!

G. Cavitation Definition!!!

A<B!*%0-&%(!1)9-')'-#&!)(!)'!2%)('!#&%!-&(')&1%!#0!3+332%!0#.$)'-#&!&#'%*!#&!9)29%!12#(-&,!

#+'!#0!%9%.7!'%&!1712%(!('+*-%*:!

! DL


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

H. Description of Detector!!!

c%!.%1#$$%&*!'/)'!7#+!*%(1.-3%!'/%!1)9-')'-#&!*%'%1'-#&!(7('%$!)&*!-&*-1)'%!-'(!(%&(-'-9-'7:!

!

I. Pressure Profile!!!

c%!.%1#$$%&*!'/)'!7#+!8.#9-*%!)!8.#0-2%!#0!'/%!8.%((+.%!9(:!'-$%!?)9%.),%*!#9%.!'%&!

1#&(%1+'-9%!(7('#2-1!1712%(F!)'!KL6!$$@,G!)&*!)'!)&7!8%)=!9%&'.-1+2).!8.%((+.%!)'!4/-1/!

1)9-')'-#&!-(!0#+&*!0#.!)&7!9)29%G!%-'/%.!(+3l%1'!#.!.%0%.%&1%:!!c%!)2(#!.%1#$$%&*!'/)'!7#+!

.%8#.'!'/%!)9%.),%!8.%((+.%!#9%.!(7('#2%:!!!

!

J. Ventricular Pressure!!!

Q)29%(!(/#+2*!3%!'%('%*!)'!KL6!$$@,!8%)=!9%&'.-1+2).!1/)$3%.!8.%((+.%!)&*!)'!)!$)Y-$+$!

02#4!.)'%!#0!T:6!IO$-&:!!\/%!(7('#2-1!.)'-#!(/#+2*!3%!(%'!)'!DE!t!L!o:!

!

K. Maximum Ventricular Pressure!!!

U0!1)9-')'-#&!-(!&#'!#3(%.9%*!-&!%-'/%.!'/%!(%'!#0!(+3l%1'!9)29%(!#.!'/%!(%'!#0!.%0%.%&1%!9)29%(G!

'/%!8%)=!9%&'.-1+2).!8.%((+.%!(/#+2*!3%!-&1.%)(%*!+&'-2!1)9-')'-#&!-(!(%%&!-&!)'!2%)('!#&%!(%'!#0!

'/%!9)29%(G!#.!+&'-2!8%)=!9%&'.-1+2).!8.%((+.%!-(!%P+)2!'#!L66!$$@,:!!U0!7#+!9).7!(7('%$!

8).)$%'%.(!'#!)1/-%9%!1)9-')'-#&G!4%!.%1#$$%&*!'/)'!7#+!*%(1.-3%!'/%!(7('%$!8).)$%'%.(!

7#+!1/)&,%*:!

! DD


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

Appendix C. Bernoulli Verification!

!

"2-&-1)2!/%$#*7&)$-1!%9)2+)'-#&!#0!.%82)1%$%&'!/%).'!9)29%(!-&!12-&-1)2!'.-)2(!'78-1)227!-&12+*%(!

$%)(+.%$%&'!#0!'/%!8.%((+.%!,.)*-%&'!37!<#882%.!+2'.)(#+&*:!!<#882%.!9%2#1-'7!$%)(+.%$%&'(!

).%!1#&9%.'%*!-&'#!8.%((+.%!,.)*-%&'(!+(-&,!'/%!_%.&#+22-!%P+)'-#&G!![!n!]?Q*L!C!Q8

LF:!!

\/%#.%'-1)227G!'/%!1#&(')&'!]!4-22!%P+)2!ZG!3+'!9)29%C*%8%&*%&'!*%9-)'-#&(!0.#$!'/-(!9)2+%!/)9%!

3%%&!.%8#.'%*:LZGLEGLHGLT

!!c%!.%1#$$%&*!'/)'!7#+!*%'%.$-&%G!*5'6*,$1G!4/%'/%.!'/%!1#%00-1-%&'!Z!-(!

)88.#8.-)'%G!37!1#$8).-&,!![!$%)(+.%*!37!<#882%.!4-'/!'/)'!$%)(+.%*!*-.%1'27!37!)!8)-.!#0!8.%((+.%!'.)&(*+1%.(:!

!

\%('-&,!(/#+2*!-&12+*%!#&%!#0!'/%!2).,%('G!-&'%.$%*-)'%G!)&*!($)22%('!()$82%(!0#.!%)1/!9)29%!'78%G!

)(!4%22!)(!)&!)88.#8.-)'%!?()$%!(-g%!)&*!'78%F!2%,)227!$).=%'%*!9)29%!)(!.%0%.%&1%:!

!

c%!.%1#$$%&*!'/)'!7#+!82#'!'/%!9)2+%(!#0!![!)(!$%)(+.%*!37!8.%((+.%!'.)&(*+1%.(!),)-&('!?Q*L!C!

Q8LF!)(!$%)(+.%*!37!<#882%.G!0#.!02#4!.)'%(!'/)'!7#+!+(%*:!

!

c%!.%1#$$%&*!'/)'!7#+!*%(1.-3%!/#4!'/%!.%(+2'-&,!%Y8%.-$%&')227!$%)(+.%*!1#&(')&'!]!$)7!

)00%1'!12-&-1)2!$%)(+.%$%&'(!#0!8.%((+.%!,.)*-%&'(G!0#.!*-),&#(-(!)&*!8.#,&#(-(.!

!

!LZ!W)$)(/-')!\G!>#.-7)$)!WG!;)')!^G!%'!)2:!<-(1.%8)&17!3%'4%%&!<#882%.!)&*!1)'/%'%.!

$%)(+.%$%&'(!#0!8.%((+.%!,.)*-%&'(!)1.#((!($)22C(-g%!8.#('/%'-1!9)29%:!!a8&!a!\/#.)1!").*-#9)(1!

;+.,:!L66EkEDNHZCM:!LE>)(1/%.3)+%.!aG!;1/-$)!@G!>)+.%.!VG!_)+$,).'&%.!@:!!<#882%.!)((%(($%&'!#0!$%1/)&-1)2!

)#.'-1!9)29%!8.#('/%(%(N!%00%1'!#0!9)29%!*%(-,&!)&*!(-g%!#0!'/%!)#.'):!!a!@%).'!Q)29%!<-(:!

L66ZkKDNMLDCD6:!!!LH;'%4).'!;AG!@%.$)&!_BG!^%22!<>G!J%'')!;>:!S00%1'(!#0!9)29%!1/).)1'%.-('-1(!#&!'/%!)11+.)17!

#0!'/%!_%.&#+22-!%P+)'-#&N!)!(+.9%7!#0!*)')!(+3$-''%*!'#!'/%!`:;:!A<B:!!a!@%).'!Q)29%!<-(:!

L66ZkKDNZHKCH:!LT_%1/C@)&((%&!RG!")-*)/2!]G!c)22%&'-&!UG!_.)&*3%.,!aG!c.)&&%!_G!B(=![:!!B#.'-1!8.#('/%'-1!

9)29%!*%(-,&!)&*!(-g%N!.%2)'-#&!'#!<#882%.!%1/#1).*-#,.)8/-1!0-&*-&,(!)&*!8.%((+.%!.%1#9%.7C!)&!

*5'6*,$1!('+*7:!!a!B$!;#1!S1/#1).*-#,.:!L666kKDND5CE6:!

! DZ


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

Appendix D. Echocardiography Protocol

!

W#+!$+('!(+3$-'!7#+.!12-&-1)2!8.#'#1#2(!4-'/!7#+.![>B!)882-1)'-#&!?LK!"AJ!MKZ:L6?3F?HF?--FF:!!

A#.!7#+.!U<S!)882-1)'-#&G!7#+!$+('!(+3$-'!)&!)11+.)'%!(+$$).7!#0!7#+.!8.#'#1#2(G!)&*!4%!$)7!

.%P+%('!)**-'-#&)2!-&0#.$)'-#&!1#&1%.&-&,!'/%!-&9%('-,)'-#&:!!LK!"AJ!MKL:L6?3F?LFG!?1FF:!!\/-(!

)88%&*-Y!*%(1.-3%(!A<Bf(!.%1#$$%&*)'-#&(!0#.!'/%!%1/#1).*-#,.)8/-1!%9)2+)'-#&!#0!

.%82)1%$%&'!/%).'!9)29%(!-&!12-&-1)2!('+*-%(:!!U&0#.$)'-#&!.%,).*-&,!'/%!%1/#1).*-#,.)8/7!

8.#'#1#2!?.%1#.*-&,!('+*-%(G!*)')!1#22%1'-#&G!)&*!1#.%!2)3#.)'#.7!1)21+2)'-#&(!)&*!)&)27(-(F!1)&!3%!

0#+&*!-&!B&&%Y!@!#0!U;R!EMZ6NL66E:!!!

!

c%!.%1#$$%&*!'/%!0#22#4-&,!-&!)**-'-#&!'#!U;R!EMZ6NL66E!B&&%Y!@G!(+3(%1'-#&!@:K:!!\/%!

.%1#$$%&*)'-#&(!)&*!$%'/#*#2#,-%(!).%!)882-1)32%!'#!)22!.%82)1%$%&'!/%).'!9)29%(!.%,).*2%((!#0!

-$82)&')'-#&!$%'/#*:!

!

B&!%1/#1).*-#,.)8/7!1#.%!2)3#.)'#.7!(/#+2*!8%.0#.$!'/%!1%&'.)2!.%9-%4!#0!)22!%1/#1).*-#,.)8/-1!

*)'):!!\/%!1#.%!2)3#.)'#.7!(/#+2*!/)9%!)!(+8%.9-(-&,!*-.%1'#.!4/#!-(!)&!%1/#1).*-#2#,-('!

%Y8%.-%&1%*!-&!%1/#1).*-#,.)8/-1!.%82)1%$%&'!9)29%!%9)2+)'-#&:!!\/%!1#.%!2)3#.)'#.7!(/#+2*!+(%!

)!4.-''%&!%1/#1).*-#,.)8/7!8.#'#1#2G!0#22#4%*!37!)22!(#&#,.)8/%.(!)&*!-&9%('-,)'#.(!-&9#29%*!-&!

'/%!12-&-1)2!('+*7:!!U&'%.8.%')'-#&!#0!'/%!%1/#1).*-#,.)$(!37!'/%!1#.%!2)3#.)'#.7!(/#+2*!3%!

$)(=%*:!!U0!'/%.%!).%!)&7!*-00%.%&1%(!3%'4%%&!'/%!('+*7!1%&'%.(!)&*!'/%!1#.%!2)3#.)'#.7!-&!'/%!

-&'%.8.%')'-#&!#0!%1/#1).*-#,.)$(G!'/%&!'/%!1#.%!2)3#.)'#.7!4-22!')=%!8.%1%*%&'!-&!A<Bf(!.%9-%4!

#0!'/%!%1/#1).*-#,.)$(:!!

!

c%!.%1#$$%&*!'/)'!7#+!('.)'-07!)22!%1/#1).*-#,.)8/-1!/%$#*7&)$-1!*)')G!-&12+*-&,!9)29+2).!

.%,+.,-')'-#&!*)')G!37!9)29%!8#(-'-#&!)&*!9)29%!(-g%:!

!

U0!7#+!1#22%1'!'.)&(%(#8/),%)2!%1/#1).*-#,.)8/7!?\SSF!*)')G!4%!.%1#$$%&*!+(-&,!)!$+2'-82)&%!

\SS!%Y)$(G!.)'/%.!'/)&!$#&#82)&%!#.!3-82)&%!\SS!%Y)$(:!!>)&7!(')&*).*!/%$#*7&)$-1!

$%)(+.%$%&'(G!(+1/!)(!)#.'-1!9)29%!8.%((+.%!,.)*-%&'(G!'/)'!).%!)9)-2)32%!4-'/!'/%!+(%!#0!

'.)&('/#.)1-1!%1/#1).*-#,.)8/7!?\\SF!$)7!&#'!3%!)9)-2)32%!-0!7#+!+(%!\SS:!!;-&1%!-'!-(!-$8#.')&'!

'#!+(%!'/%!()$%!%1/#1).*-#,.)8/-1!-$),-&,!$#*)2-'7!)'!)22!0#22#4C+8!'-$%C8#-&'(G!)&*!(-&1%!\\S!

-(!'/%!12-&-1)2!(')&*).*!)&*!2%)('!-&9)(-9%!$%'/#*!#0!%1/#1).*-#,.)8/7G!4%!.%1#$$%&*!'/)'!7#+!

8%.0#.$!\\S!%Y)$(!)'!)22!0#22#4C+8!'-$%!8#-&'(:!!\/%(%!'-$%!8#-&'(!(/#+2*!-&12+*%!h)'!/#(8-')2!

*-(1/).,%i!#.!)!'-$%!8#-&'!)'!D6!*)7(!#.!2%((!8#('C-$82)&'!-0!'/%!(+3l%1'!/)(!&#'!3%%&!*-(1/).,%*:!

!

A. Data Collected by the Study Center

U0!7#+!0#22#4!U;R!EMZ6NL66E!B&&%Y!@G!(+3(%1'-#&!@:DG!4%!.%1#$$%&*!'/%!)**-'-#&(!

*%(1.-3%*!3%2#4:!

!

<)')!1#22%1'%*!37!'/%!('+*7!1%&'%.!(/#+2*!-&12+*%N!!

! 8%)=!8.%((+.%!,.)*-%&'!

! $%)&!8.%((+.%!,.)*-%&'!

! DE


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

! %00%1'-9%!#.-0-1%!).%)!?SRB!#.!BSRF!

! %00%1'-9%!#.-0-1%!).%)!-&*%Y!?SRBU!#.!BSRUF!

! 8%.0#.$)&1%!-&*%Y!?[UF!

! 1).*-)1!#+'8+'!?"R!#.!R"F!

! 1).*-)1!-&*%Y!?"UF:!!!

!\/%!*)')!(/#+2*!1#&(-('!#0!(+3l%1'!&+$3%.(!)&*!$%)&!?)9%.),%FG!(')&*).*!*%9-)'-#&G!

$-&-$+$!9)2+%(G!)&*!$)Y-$+$!9)2+%(:!!c%!.%1#$$%&*!'/)'!7#+!('.)'-07!'/%!*)')!37!9)29%!

8#(-'-#&!)&*!9)29%!(-g%:!!!

!

B2'/#+,/!U;R!EMZ6NL66E!+(%(!'/%!'%.$(!h9%2#1-'7!-&'%,.)2i!)&*!hr*-)('#2-1s!9%2#1-'7!-&'%,.)2!

?<QUFGi!'/%!1#$$#&!`:;:!12-&-1)2!'%.$!-(!h9%2#1-'7!'-$%!-&'%,.)2!?Q\UFi!#.!h'-$%!9%2#1-'7!

-&'%,.)2!?\QUF:i

!

U;R!EMZ6NL66E!.%1#$$%&*(!)9%.),-&,!E!/%).'!3%)'(!4/%&!#3')-&-&,!%1/#1).*-#,.)8/-1!

/%$#*7&)$-1!$%)(+.%$%&'(!-&!(+3l%1'(!4-'/!)'.-)2!0-3.-22)'-#&:!!\/%(%!(+3l%1'(!$)7!/)9%!)!

/-,/27!9).-)32%!/%).'!.)'%!4/-1/!$)7!1)+(%!$%)(+.%$%&'(!'/)'!).%!%-'/%.!(%9%.)2!$-&+'%(!

)8).'!?(+1/!)(!IQR\!)&*!$-'.)2!9)29%!$%)(+.%$%&'(F!#.!#3')-&%*!#9%.!E!#.!$#.%!3%)'(:!!;+1/!

$%)(+.%$%&'(!$)7!3%!%..#&%#+(!3%1)+(%!'/%7!).%!(+3l%1'!'#!3#'/!/%).'!.)'%!9).-)'-#&!)&*!

.%(8-.)'#.7!)2'%.)'-#&:!!U&!#.*%.!'#!$-'-,)'%!$%)(+.%$%&'!%..#.(G!'/%!%1/#1).*-#,.)8/%.!(/#+2*!

(%2%1'!3%)'(!'/)'!0#22#4!)!8/7(-#2#,-1!8.%1%*-&,!1712%!2%&,'/!?%:,:G!M66!t!M6!$(!#.!TE!t!K6!

38$F!#.!3%)'(!4-'/!K6o!9).-)3-2-'7!-&!/%).'!.)'%:!!`(-&,!%-'/%.!#0!'/%(%!'4#!)88.#)1/%(G!'/%!

(')&*).*!$+2'-82%!3%)'(!?+(+)227!DF!1)&!3%!$%)(+.%*!)&*!)9%.),%*!.%,).*2%((!#0!'/%!

+&*%.27-&,!./7'/$:!

!

Q)29+2).!.%,+.,-')'-#&!*)')!(/#+2*!1#&(-('!#0!'/%!&+$3%.(!)&*!8%.1%&'),%(!#0!(+3l%1'(!0#.!

%)1/!,.)*%!#0!(%9%.-'7:!!c%!.%1#$$%&*!'/)'!7#+!('.)'-07!9)29+2).!.%,+.,-')'-#&!*)')!37!,.)*%!

#0!.%,+.,-')'-#&!(%9%.-'7G!9)29%!8#(-'-#&G!)&*!9)29%!(-g%:!

!

c%!.%1#$$%&*!'/)'!7#+!*#1+$%&'!#'/%.!*)')!'/)'!).%!.#+'-&%27!#3')-&%*!)(!8).'!#0!)!

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! &#&C('+*7!9)29%!?&)'-9%!#.!#'/%.!.%82)1%$%&'F!('.+1'+.%!)&*!0+&1'-#&!

! 2%0'!)&*!.-,/'!)'.-)2!(-g%!

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!

1. Effective Orifice Area

c%!.%1#$$%&*!'/)'!7#+!8%.0#.$!%1/#1).*-#,.)8/-1!('+*-%(!)(!*%(1.-3%*!-&!U;R!

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7#+!8%.0#.$!'/%!1#.%!2)3#.)'#.7!1)21+2)'-#&(!)&*!)&)27(%(!)(!*%(1.-3%*!3%2#4:!!!

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A#.!%00%1'-9%!#.-0-1%!).%)G!BSRG!4%!.%1#$$%&*!'/%!1#&'-&+-'7!%P+)'-#&!3%2#4:!

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2-=%27!#9%.%('-$)'%!'/%!$-'.)2!9)29%!%00%1'-9%!#.-0-1%!).%)G!-0!7#+!+(%!'/%!IQR\!1.#((C

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IN PLACE OF: USE:

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)&&+2+(!-&!1$!0#.!'/%!$-'.)2!('.#=%!9#2+$%!1)21+2)'-#&!

C?2! -(!'/%!IQR\!9%2#1-'7!'-$%!-&'%,.)2!-&!1$!0#.!'/%!)#.'-1!

('.#=%!9#2+$%!1)21+2)'-#&G!#.!'/%!$-'.)2!9%2#1-'7!'-$%!

-&'%,.)2!-&!1$!0#.!'/%!$-'.)2!('.#=%!9#2+$%!1)21+2)'-#&!

!

6. Cardiac Index

c%!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'/%!1).*-)1!-&*%Y!)(!0#22#4(N!

!

!IE

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F

<=2 $ ! !

!

4/%.%! =2!! ! -(!'/%!1).*-)1!-&*%Y!-&!2O$-&O$L!

!

! <"!! ! -(!'/%!1).*-)1!#+'8+'!-&!2O$-&!

!

F_;!! ! -(!'/%!3#*7!(+.0)1%!).%)!-&!$L!

!

7. Performance Index

c%!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'/%!8%.0#.$)&1%!-&*%Y!)(!0#22#4(N!

!

!HC

:<

2<F

F6*61*5H2 $ ! !

!

4/%.%! H2'! ! -(!'/%!8%.0#.$)&1%!-&*%YG!4/-1/!/)(!&#!*-$%&(-#&(!

!

*5'6*61!FSR! -(!'/%!*5'6*61!%00%1'-9%!#.-0-1%!).%)!-&!1$L!

!

2<F[Q! -(!'/%!8.%C-$82)&'!-&'%.&)2!#.-0-1%!).%)!#0!'/%!.%82)1%$%&'!

9)29%!-&!1$LG!#3')-&%*!0.#$!'/%!.%82)1%$%&'!9)29%!

(8%1-0-1)'-#&(!

!

A#.!.%82)1%$%&'!8+2$#&-1!9)29%(!)&*!8+2$#&-1!9)29%*!1#&*+-'(G!4%!*#!&#'!.%1#$$%&*!

'/)'!7#+!1)21+2)'%!'/%!8%.0#.$)&1%!-&*%YG!4/-1/!-(!1)21+2)'%*!+(-&,!%00%1'-9%!#.-0-1%!).%)!

*)')G!(-&1%!'/%!1#&%!(/)8%!#0!'/%!.-,/'!9%&'.-1+2).!#+'02#4!'.)1'!$)=%(!%1/#1).*-#,.)8/-1!

$%)(+.%$%&'!#0!'/%!.-,/'!9%&'.-1+2).!#+'02#4!'.)1'!*-)$%'%.!*-00-1+2':!!\/-(!*-00-1+2'!

! ZL


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

$%)(+.%$%&'!2%)*(!'#!8#'%&'-)2!-&)11+.)'%!1)21+2)'-#&!#0!'/%!8+2$#&-1!9)29%!%00%1'-9%!

#.-0-1%!).%)!9-)!'/%!1#&'-&+-'7!%P+)'-#&!$%'/#*:!

!

C. Valvular Regurgitation

U&!)**-'-#&!'#!U;R!EMZ6NL66EG!;%1'-#&!@:ZG!(+3(%1'-#&!@:Z:TG!4%!.%1#$$%&*!'/)'!7#+!

-&12+*%!'/%!-&0#.$)'-#&!*%(1.-3%*!3%2#4!-&!7#+.!%9)2+)'-#&!#0!9)29+2).!.%,+.,-')'-#&:!

!

c%!.%1#$$%&*!'/)'!7#+!-*%&'-07!%)1/!l%'!)(!8%.-9)29+2).G!'.)&(9)29+2).G!3#'/G!#.!+&1%.')-&:!!

c%!)2(#!.%1#$$%&*!'/)'!7#+!(/#4!'/%!(-'%!#0!%)1/!8%.-9)29+2).!l%'!#&!'/%!(%4-&,!.-&,G!0#.!

%Y)$82%G!)(!)!q12#1=C0)1%q!*-),.)$:!!!

\/%!%9)2+)'-#&!#0!9)29+2).!.%,+.,-')'-#&!(/#+2*!-&9#29%!)&!-&'%,.)'%*!)88.#)1/!-&!4/-1/!7#+!

+(%!$+2'-82%!%1/#1).*-#,.)8/-1!$%'/#*(!'#!)((%((!.%,+.,-')'-#&!)'!%)1/!0#22#4C+8!'-$%C8#-&':!!

;-&1%!1%.')-&!$%'/#*(!$)7!&#'!3%!)9)-2)32%!)'!%9%.7!0#22#4C+8!9-(-'G!'/-(!)88.#)1/!)22#4(!7#+!

'#!1#$8).%!(%P+%&'-)2!.%(+2'(!0#.!'/%!%&'-.%!*+.)'-#&!#0!0#22#4C+8G!4-'/!'/%!.%(+2'(!#3')-&%*!37!

'/%!()$%!$%'/#*!#.!$%'/#*(:!!c%!.%1#$$%&*G!/#4%9%.G!'/)'!7#+!(+3$-'!)22!0#22#4C+8!

.%(+2'(G!-&12+*-&,!'/#(%!#3')-&%*!37!$%'/#*(!4-'/!$-((-&,!'-$%C8#-&'(:!!B88.#8.-)'%!$%'/#*(!

0#.!%9)2+)'-&,!.%,+.,-')'-#&!).%!(+$$).-g%*!3%2#4!)&*!*-(1+((%*!-&!0+.'/%.!*%')-2!-&!'/%!

2-'%.)'+.%:D6GDK

!

1. Aortic Regurgitation

c%!.%1#$$%&*!'/)'!7#+!,.)*%!)#.'-1!.%,+.,-')'-#&!37!)&!-&'%,.)'%*!%9)2+)'-#&!3)(%*!#&!

0)1'#.(!-&12+*-&,N!!

! -&('.+$%&'!(%''-&,!

! l%'!4-*'/!

! l%'!).%)!

! l%'!*%8'/!

! '/%!(/)8%!?1#&'#+.F!)&*!'/%!*%&(-'7!#0!'/%!1#&'-&+#+(!4)9%!(-,&)2!?%:,:G!'/%!

*%1%2%.)'-#&!'-$%!)&*!8.%((+.%!/)20C'-$%!3#'/!*%1.%)(%!4-'/!-&1.%)(-&,!BJ!(%9%.-'7k!

-&1.%)(%*!(-,&)2!*%&(-'7!,%&%.)227!-&*-1)'%(!$#.%!(%9%.%!BJF!

! '/%!*+.)'-#&!#0!'/%!1#&'-&+#+(!4)9%!(-,&)2!?%:,:G!)!3.-%0!*-)('#2-1!*+.)'-#&!+(+)227!

-&*-1)'%(!8/7(-#2#,-1!#.!$-2*!BJF!

!D6!b#,/3-!cBG!S&.-P+%gC;).)&#!>G!A#('%.!SG!V.)73+.&![BG!].)0'!"<G!I%9-&%!JBG!

^-/#7)&&#8#+2#(![G!R''#!">G!d+-&#&%(!>BG!J)=#4(=-!@G!;'%4).'!caG!c),,#&%.!BG!)&*!

c%-(($)&!â:!J%1#$$%&*)'-#&(!0#.!%9)2+)'-#&!#0!'/%!(%9%.-'7!#0!&)'-9%!9)29+2).!.%,+.,-')'-#&!

4-'/!'4#C*-$%&(-#&)2!)&*!<#882%.!%1/#1).*-#,.)8/7:!a!B$!;#1!S1/#1).*-#,.!KHNTTTCM6LG!

L66D:!DK!V#''*-%&%.!a;G!_%*&).g!aG!<%9%.%+Y!JG!V).*-&!aG!]2%-&!BG!>)&&-&,!caG!>#.%/%)*!BG!]-'g$)&!

<G!R/!aG!d+-&#&%(!>G!;1/-22%.!^_G!;'%-&!a@G!)&*!c%-(($)&!â:!B$%.-1)&!;#1-%'7!#0!

S1/#1).*-#,.)8/7!.%1#$$%&*)'-#&(!0#.!+(%!#0!%1/#1).*-#,.)8/7!-&!12-&-1)2!'.-)2(G!a!B$!;#1!

S1/#1).*-#,.!KTNK6MHCKKK5G!L66Z:!

! ZD


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

! '/%!('.+1'+.%!#0!'/%!)#.'-1!9)29%!

! '/%!(-g%!)&*!0+&1'-#&!#0!'/%!2%0'!9%&'.-12%!

! /#4!0).!*-)('#2-1!02#4!.%9%.()2!1)&!3%!9-(+)2-g%*!4-'/-&!'/%!)#.'):DL!!!

!

R0!'/%(%!,.)*-&,!0)1'#.(G!'/%!4-*'/!#0!'/%!)#.'-1!l%'!)(!)!8.#8#.'-#&!#0!'/%!2%0'!9%&'.-1+2).!

#+'02#4!'.)1'!*-)$%'%.!-(!'/%!$#('!0.%P+%&'27!+(%*!(-&,2%!$%)(+.%:DD!!@#4%9%.G!l%'!4-*'/!

(/#+2*!3%!)882-%*!1).%0+227!0#.!%11%&'.-1!l%'(:!!!

!

c%!.%1#$$%&*!'/)'!7#+!)2(#!,.)*%!)#.'-1!.%,+.,-')'-#&!37!'/%!)88%).)&1%!#0!'/%!*-)('#2-1!

0-22-&,!8)''%.&!-&!$-'.)2!-&02#4!?%:,:G!(%9%.%!)#.'-1!.%,+.,-')'-#&!.%(+2'(!-&!)!.%('.-1'-9%!$-'.)2!

0-22-&,!8)''%.&!4-'/!/-,/!S!9%2#1-'7G!2#4!B!9%2#1-'7G!-&1.%)(%*!SOB!9%2#1-'7!.)'-#G!)&*!(/#.'!

*%1%2%.)'-#&!'-$%F:!!!

!

c%!)2(#!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'/%!.%,+.,-')&'!9#2+$%G!.%,+.,-')&'!0.)1'-#&G!)&*!

%00%1'-9%!.%,+.,-')&'!#.-0-1%G!'#!#3')-&!)!$#.%!#3l%1'-9%!P+)&'-g)'-#&!#0!'/%!(%9%.-'7!#0!)#.'-1!

.%,+.,-')'-#&:!!\/%!.%,+.,-')&'!9#2+$%G!.%,+.,-')&'!0.)1'-#&G!)&*!%00%1'-9%!.%,+.,-')&'!

#.-0-1%!).%)!1)&!3%!1)21+2)'%*!37!'/%!9#2+$%'.-1!#.!8.#Y-$)2!-(#9%2#1-'7!(+.0)1%!).%)!?[U;BF!

$%'/#*(:!!^#.$)2!.%,+.,-')'-#&!*+%!'#!3)1=02#4!(/#+2*!3%!*-('-&,+-(/%*!0.#$!8)'/#2#,-1!

.%,+.,-')'-#&:!!\/%!+(+)2!*-('-&,+-(/-&,!0%)'+.%(!#0!&#.$)2!.%,+.,-')'-#&!).%!)!+&-0#.$!1#2#.!

8)''%.&!)&*!($)22!l%'(!4-'/!&#.$)2!.%,+.,-')'-#&:!!\/%!+(+)2!*-('-&,+-(/-&,!0%)'+.%(!#0!

8)'/#2#,-1!.%,+.,-')'-#&!).%!)!$#()-1!1#2#.!8)''%.&!)&*!2).,%.!l%'(:!!!

!

2. Mitral Regurgitation

c%!.%1#$$%&*!'/)'!7#+!,.)*%!$-'.)2!.%,+.,-')'-#&!37!)&!-&'%,.)'%*!%9)2+)'-#&!3)(%*!#&!

0)1'#.(G!-&12+*-&,N!

! -&('.+$%&'!(%''-&,!

! l%'!4-*'/!

! l%'!).%)!

! l%'!*%8'/!

! l%'!%11%&'.-1-'7!

! '/%!(/)8%!?1#&'#+.F!)&*!'/%!*%&(-'7!#0!'/%!1#&'-&+#+(!4)9%!(-,&)2!?%:,:G!(%9%.%!$-'.)2!

.%,+.,-')'-#&!$)7!.%(+2'!-&!)!q1+'C#00!(-,&i!*+%!'#!)!2).,%!9!4)9%k!-&1.%)(%*!(-,&)2!

*%&(-'7!,%&%.)227!-&*-1)'%(!$#.%!(%9%.%!>JF!

! '/%!8%)=!9%2#1-'7!#0!'/%!1#&'-&+#+(!4)9%!(-,&)2!?%:,:G!8%)=!9%2#1-'7!*%1.%)(%(!4-'/!

-&1.%)(-&,!$-'.)2!.%,+.,-')'-#&!(%9%.-'7!*+%!'#!-&1.%)(%*!2%0'!)'.-)2!8.%((+.%F!

! '/%!*+.)'-#&!#0!'/%!1#&'-&+#+(!4)9%!(-,&)2!

! '/%!('.+1'+.%!#0!'/%!$-'.)2!9)29%!

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9)29%!.%,+.,-')'-#&!37!%1/#!<#882%.!'%1/&-P+%(G!_.-'!@%).'!a!!TD?E!;+882!LFNKC5G!K55E:!DD![%..7!VaG!@%2$1=%!AG!^)&*)!^"G!_7).*!"G!)&*!;#'#!_:!!S9)2+)'-#&!#0!)#.'-1!-&(+00-1-%&17!37!

<#882%.!1#2#.!02#4!$)88-&,G!a!B$!"#22!").*-#2!5N5ELC5E5G!K5MT:!

! ZZ


-$%.,'/'01,'.1$'234&"3"5,%,*15'

!

! ZE

! '/%!(-g%!)&*!0+&1'-#&!#0!'/%!2%0'!9%&'.-12%!

! '/%!(-g%!#0!'/%!2%0'!)'.-+$!

! -$8-&,%$%&'!#0!'/%!l%'!#&!'/%!2%0'!)'.-)2!4)22!

! '/%!*-.%1'-#&!#0!(7('#2-1!02#4!-&!'/%!8+2$#&).7!9%-&(!?%:,:G!(%9%.%!$-'.)2!.%,+.,-')'-#&!

$)7!.%(+2'!-&!(7('#2-1!02#4!.%9%.()2F!

! '/%!4-*'/!#0!'/%!9%&)!1#&'.)1')!?'/%!&)..#4%('!8#.'-#&!#0!'/%!$-'.)2!.%,+.,-')'-#&!l%'!

*#4&('.%)$!0.#$!'/%!#.-0-1%F:!!!

!

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$-'.)2!-&02#4!?%:,:G!(%9%.%!$-'.)2!.%,+.,-')'-#&!.%(+2'(!-&!)!.%('.-1'-9%!0-22-&,!8)''%.&!4-'/!

/-,/!S!9%2#1-'7G!2#4!B!9%2#1-'7G!-&1.%)(%*!SOB!.)'-#G!)&*!(/#.'!*%1%2%.)'-#&!'-$%F:!!!

!

c%!)2(#!.%1#$$%&*!'/)'!7#+!1)21+2)'%!'/%!.%,+.,-')&'!9#2+$%G!.%,+.,-')&'!0.)1'-#&G!)&*!

%00%1'-9%!.%,+.,-')&'!#.-0-1%!'#!#3')-&!)!$#.%!#3l%1'-9%!P+)&'-')'-#&!#0!'/%!(%9%.-'7!#0!$-'.)2!

.%,+.,-')'-#&:!!\/%!.%,+.,-')&'!9#2+$%G!.%,+.,-')&'!0.)1'-#&G!)&*!%00%1'-9%!.%,+.,-')&'!

#.-0-1%!1)&!3%!1)21+2)'%*!37!'/%!9#2+$%'.-1!#.![U;B!$%'/#*(:!!^#.$)2!.%,+.,-')'-#&!*+%!'#!

3)1=02#4!(/#+2*!3%!*-('-&,+-(/%*!0.#$!8)'/#2#,-1!.%,+.,-')'-#&:!!\/%!+(+)2!*-('-&,+-(/-&,!

0%)'+.%(!#0!&#.$)2!.%,+.,-')'-#&!).%!)!+&-0#.$!1#2#.!8)''%.&!)&*!($)22!l%'(!4-'/!&#.$)2!

.%,+.,-')'-#&:!!\/%!+(+)2!*-('-&,+-(/-&,!0%)'+.%(!#0!8)'/#2#,-1!.%,+.,-')'-#&!).%!)!$#()-1!

1#2#.!8)''%.&!)&*!2).,%.!l%'(:!!!