WARNING LETTER. used i

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1 DEPARTMENT OF HEALTH & HUMAN SERVICES Pub l i c Hea l th Serv i ce Food and Drug Admi n i st ra t i on OCT Center for Dev i ces and Rad i o l og i ca l Hea l th WARNING LETTER 2098 Ga i ther Road Rockv i l l e, MD VIA FEDERAL EXPRESS Reyna l do F. Mu l i ngtapang. M.D. 4 Co l umb i a Dr i ve Tampa, F l or i da Dear Dr. Mu l i ngtapang : The purpose of th i s Warn i ng Le t ter i s to i nform you of ob j ec t i onab l e cond i t i ons found dur i ng a Food and Drug Admi n i st ra t i on (FDA) i nspec t i on conduc ted a t Un i vers i ty of South F l or i da (USF), D i v i s i on of Card i ovascu l ar D i sease_ An i nvest i ga tor f rom FDA' s F l or i da D i st r i c t Of f i ce conduc ted the i nspec t i on f rom June 7 through June The purpose of. the i nspec t i on was to de termi ne i f your ac t _ ~ i. ṿ : ị _ t._. i es as a c l i n i ca l i nvest i ga tor for the used i " comp l i ed w i th app l i cab l e FDA i s a dev i ce de f i ned i n Sec t i on 201(h) of the Federa l Food, Drug, and Cosme t i c Ac t ( the Ac t ) [21 U.S.C. 321(h) ]. Th i s l e t ter a l so d i scusses your wr i t ten response da ted June 24, 2005, to the noted v i o l a t i ons and requests tha t you i mp l ement prompt cor rec t i ve ac t i ons. The FDA conduc ted the i nspec t i on under a program des i gned to ensure tha t da ta and i nforma t i on conta i ned i n requests for Invest i ga t i ona l Dev i ce Exempt i ons ( IDE), Premarke t Approva l App l i ca t i ons (PMA), and Premarke t Not i f i ca t i on [510(k) ] submi ss i ons are sc i ent i f i ca l l y va l i d and accura te. The program a l so ensures tha t human sub j ec ts are protec ted f rom undue hazard or r i sk dur i ng sc i ent i f i c i nvest i ga t i ons. Our rev i ew of the i nspec t i on repor t prepared by the d i st r i c t of f i ce revea l ed ser i ous v i o l a t i ons of T i t l e 21, Code of Federa l Regu l a t i ons (21 CFR), Par t 812- Invest i ga t i ona l Dev i ce Exempt i ons and Par t 50-Protec t i on of Hurnan Sub j ec ts. At the c l ose of the i nspec t i on, the FDA i nvest i ga tor presented a Form FDA 483 " Inspec t i ona l Observa t i ons" to you for rev i ew and d i scussed the l i sted dev i a t i ons. The dev i a t i ons noted on the Form FDA 483 and our subsequent i nspec t i on repor t rev i ew are d i scussed be l ow : Fa i l ure to obta i n proper i nformed consent for 3 of 5 study sub j ec ts. [21 CFR 50.20, , and (a) (3) ( i ) ] Invest i ga tors are respons i b l e for ensur i ng tha t i nformed consent i s obta i ned and tha t records of i nformed consent are kept i n accordance w i th FDA regu l a t i ons 21 CFR 50.20,

2 Page 2 Reyna l do F. Mu l i notapang, M.D , and (a ' ) ( '3) (1). Th i s i nc l udes obta i n i ng s i gned new consent documents for sub j ec ts when the IRB approves changes i n the protoco l and accompany i ng consent document tha t a l ter the study procedures or may otherw i se a f fec t the sub j ec t ' s w i l l i ngness to par t i c i pa te. Cl i n i ca l i nvest i ga tors must i nc l ude i n each sub j ec t ' s case h i story documents ev i denc i ng tha t i nformed consent was obta i ned. You fa i l ed to obta i n sub j ec t s i gna tures on the September 16, 2004, IRB-approved vers i on of the i nformed consent document for 3 of 5 sub j ec ts. Tha t upda ted i nformed consent document prov i des new i nforma t i on i nc l ud i ng : " add i t i on of fo l l ow-up d i agnost i c procedures a t the 24 month v i s i t : Ruther ford Cl ass i f i ca t i on, Rest i ng A.BI ' s, and Index ext remi ty X-Ray. " changes i n the statement, "You w i l l not be charged for any non- rout i ne costs assoc i a ted w i th the study. These costs w i l l be covered by the spornsor. " The new statement, "You or your i nsurance company w i l l be charged for the.4w. Some i nsurance prov i ders w i l l not pay for the cost of the go. " " c l ar i f i ca t i on of the statement, "The taw&- "~ i i w i s not FDA approved for p l acement i n the but i t i s FDA approved for use i n the study. " The new statement "The~ " Ws i nvest i ga t i ona l, wh i ch means tha t i t i s not approved by the U.S. Food and Drug Admi n i st ra t i on (FDA) for p l acement i n the " and " upda ted contac t i nforma t i on for Dr. Mu l i ngtapang. In your response, you i nd i ca te tha t these three sub j ec ts were contac ted by your study coord i na tor but dec l i ned to s i gn the new consent. You fur ther i nd i ca te tha t they d i d not par t i c i pa te i n the add i t i ona l fo l l ow-up for wh i ch the new consent form a t tempted to so l i c i t consent. However., there i s no documentat i on of the sub j ec ts be i ng contac ted or w i thdrawn f rom the i nvest i ga t i on i n the case h i stor i es rev i ewed. Under the c i rcumstances you descr i be, the sub j ec t f i l es shou l d have documentat i on of the e f for ts made to obta i n consent, the sub j ec ts ' re fusa l s, and your subsequent steps to ensure tha t they were termi na ted f rom the study. " P l ease prov i de cop i es of :po l i c i es, procedures, and t ra i n i ng w i th expec ted comp l e t i on da tes, wh i ch are be i ng deve l oped and i mp l emented to ensure i nformed consent i s obta i ned and documented. Fa i l ure to ma i nta i n accura te, comp l e te, and cur rent case h i stor i es (a) (3) ] [21 CFR You fa i l ed to ma i nta i n comp l e te, cur rent, and accura te case h i story f i l es regard i ng study ac t i v i t i es requ i red by the study protoco l. Examp l es of th i s fa i l ure i nc l ude, but are not l i mi ted to the fo l l ow i ng :

3 Page 3 Reyna l do F. Mu l i ngtapang, M.D 1) The n i ne month fo l l ow-up case repor t form (CRF) to..,~1-1 i nd i ca ted the sub j ec t was contac ted by phone, however the resu l ts of Ank l e-brac l i i a l Index (ABI ) ( requ i r i ng the sub j ec t be phys i ca l l y present ) were recorded on the CRF. In your response you state the sub j ec t had the fo l l ow-up test i ng per formed but d i d not re turn for the outpa t i ent v i s i t and then w i thdrew f rom the study. You i nd i ca te tha t a nar ra t i ve por t i on of the study records documented th i s s i tua t i on. The CRF exami ned by the i nvest i ga tor for the n i ne month v i s i t notes the sub j ec t was contac ted on l y by phone. The resu l ts documented on tha t CRF cou l d not be per formed by phone contac t. There i s no source documentat i on tha t the sub j ec t ac tua l l y had the tests per formed. The nar ra t i ve form you prov i ded w i th your 483 response to suppor t your exp l ana t i on i s da ted September 17, 2004, near l y one year a f ter the sub j ec t ' s schedu l ed 9-month v i s i t and repor ted w i thdrawa l f rom the study. These records were there fore not comp l e te and cur rent. ase l i ne ' s h i story record i nd i ca tes tha t the sub j ec t was "on Coumad i n" however, the d i scharge CRF does not l i st Coumad i n as a med i ca t i on the sub j ec t i s tak i ng. There i s confus i on i n the documentat i on as to whe ther the sub j ec t was or was not on Coumad i n. In add i t i on, the n i ne month fo l l ow-up v i s i t CRF i s mi ss i ng va l ues for b l ood pressure (B/P) i n the l e f t arm, l e f t ank l e systo l i c pressure, and l e f t ABI. In your response you state, the sub j ec t stopped h i s Coumad i n 10 days pr i or to the procedure and restar ted 2 days a f ter, however, there was no source documentat i on not i ng th i s. The protoco l requ i res sub j ec ts on Coumad i n to have Interna t i ona l Norma l i zed Ra t i o ( fnr) per formed. There i s no documentat i on tha t INR ' s were per formed on th i s sub j ec t, e i ther i n the i mmed i a te post -opera t i ve per i od or a t h i s n i ne-month fo l l ow up v i s i t. In add i t i on, regu l a t i ons requ i re an i nvest i ga tor to not i fy the sponsor and the rev i ew i ng IRB of any dev i a t i on f rom the : i nvest i ga t i ona l p l an to protec t the l i fe or phys i ca l we l l -be i ng of a sub j ec t or of dev i a t i ons tha t i mpac t the sc i ent i f i c soundness of the i nvest i ga t i on. See 21 CFR (a) (4). Fa i l ure to obta i n these l abora tory tests i s a protoco l dev i a t i on and wou l d requ i re not i f i ca t i on of the sponsor and IRB, but there i s no documentat i on of such not i f i ca t i on. In add i t i on, you d i d not address mi ss i ng i nforma t i on i n the case h i story and CRY. Spec i f i ca l l y, va l ues for n i ne month fo l l ow-up of l e f t arm B/P, l e f t ank l e systo l i c pressure, and l e f t ABI. Your response i s i nadequa te ; i t does not descr i be how you are go i ng to ensure comp l e te, accura te, and cur rent documentat i on of c l i n i ca l t r i a l da ta. Documentat i on of a l l protoco l re l a ted e l ements i s a cr i t i ca l component to conduc t i ng c l i n i ca l t r i a l s i nc l ud i ng, med i ca t i ons taken, d i agnost i c procedures. adverse events, and commun i ca t i ons w i th the sub j ec ts. P l ease prov i de cop i es of po l i c i es and procedures, w i th expec ted comp l e t i on da tes tha t are be i ng deve l oped and i mp l emented to ensure proper documentat i on of protoco l re l a ted e l ements and the ma i ntenance of comp l e te, accura te, and cur rent case h i stor i es.

4 Page 4 Reyna l do F. Mu l i ngtapang, M.D. Fa i l ure to conduc t the i nvest i ga t i on accord i ng to the s i gned agreement, the i nvest i ga t i ona l p l an, and app l i cab l e FDA regu l a t i ons. [21 CFR and 21 CFR (b) ] In accordance to 21 CFR and (b), c l i n i ca l i nvest i ga tors are requ i red to ensure tha t i nvest i ga t i ons are conduc ted accord i ng to the s i gned agreement, the i nvest i ga t i ona l p l an, and app l i cab l e FDA regu l a t i ons, as we l l as any cond i t i ons of approva l i mposed by the IRB or FDA. In add i t i on, federa l regu l a t i ons requ i re tha t c l i n i ca l i nvest i ga tors obta i n pr i or approva l f rom the sponsor be fore i mp l ement i ng any dev i a t i ons f rom the i nvest i ga t i ona l p l an, except for dev i a t i ons to protec t the l i fe or phys i ca l we l l be i ng of a sub j ec t i n an emergency. (21 CFR (a) (4) ). I f these changes or dev i a t i ons a f fec t the sc i ent i f i c soundness of the p l an or the r i ghts, sa fety, or we l fare of the sub j ec ts, FDA and IRB approva l are a l so requ i red. (21 CFR (a) (4), (a) ). Our i nvest i ga t i on revea l ed severa l dev i a t i ons f rom the s i gned agreement and i nvest i ga t i ona l p l an, i nc l ud i ng but not l i mi ted to the fo l l ow i ng : 1) Under the protoco l i n e f fec t a t the t i me, i nc l us i on cr i ter i a #3 states, "Pa t i ent requ i res t rea tment of a ' ~ ' However, ha rea ted dur i ng the i ndex procedure. In your response you state tha t a t the t i me of t rea tment of th i s sub j ec t, the protoco l d i d not l i st t rea tment of bo thu r i ng the i ndex procedure as an exc l us i on cr i ter i a. You do not d i sagree tha t the i nc l us i on cr i ter i a a t the t i me re fer red to t rea tment of a~~you state tha t you d i scussed enro l l ment of th i s sub i ec t w i th the sponsor anc~ were g i ven a l l owance to t rea t l awwas per standard of care and-446p ~ as per the protoco l. However, there i s no documentat i on of th i s sponsor approva l pr i or to enro l l i ng th i s sub j ec t. You a t tached a l e t ter f rom the sponsor da ted January 28, 2003, c l ar i fy i ng t rea tment of add i t i ona l SAINDPrand stat i ng they must be t rea ted 24 hours pr i or to or a f ter the i ndex procedure, apparent l y to suppor t your v i ew tha t a t the t i me of your enro l l ment and t rea tment of th i s sub j ec t, i t was amb i guous as to whe ther or not sub j ec ts hav i ng more than~~ i n need of t rea tment were to be exc l uded. You do not appear to re l y on th i s l e t ter as grant i ng permi ss i on for the procedures done w i th regard to the sub j ec t i n quest i on, nor cou l d you, as your sub j ec t was t rea ted s i x weeks pr i or to the da te of the l e t ter, and you t rea ted both l es i ons a t the same t i me, not 24 hours apar t, as manda ted i n the sponsor ' s protoco l c l ar i f i ca t i on. Trea t i ng th i s sub j ec t was a protoco l dev i a t i on. There i s i nadequa te documentat i on of not i' f i ca t i on of the sponsor and IRB of these dev i a t i ons f rom the i nvest i ga t i ona l p l an. P l ease prov i de cop i es of po l i c i es, procedures, and t ra i n i ng w i th expec ted comp l e t i on da tes, wh i ch are be i ng deve l oped and i mp l emented to ensure dev i a t i ons f rom the i nvest i ga t i ona l p l an are repor ted i n accordance w i th the FDA regu l a t i ons and your IRB' s po l i cy.

5 Page 5 Reyna l do F. Mu l i notapang, M.D. 2) The i nvest i ga t i ona l p l an requ i res ant i c i pa ted and unant i c i pa ted adverse events and comp l i ca t i ons to be recorded on the Adverse /Ser i ous Adverse Event CRF and repor ted to the l oca l IRB and coord i na t i ng center. In add i t i on, repor t i ng of ser i ous adverse events occur r i ng i n the study are to be repor ted w i th i n 24 hours of the i nvest i ga tor ' s know l edge to the coord i na t i ng center for the pr i nc i pa l study i nvest i ga tor to rev i ew. However, you d i d not repor t ser i ous adverse events i n accordance w i th these requ i rements. For examp l e, 4pomcomp l a i ned of pa i n i n the r i ght l eg dur i ng a non-schedu l ed study v i s i t on 1/31/2005. In February, the sub j ec t was seen 'by Sub- Invest i ga to~, a t wh i ch t i me he documented c l ot t i ng of the super f i c i a l femora l ar tery, "probab l y i n the area of the stent. " The adverse event CRF was not comp l e ted unt i l the FDA i nspec t i on on 6/28/2005. P l ease note, the adverse event CRF i s mi ss i ng the da te of the event. Fur thermore, there i s no documentat i on of the event be i ng repor ted to the IRB or sponsor. In your response you note th i s event was i nadver tent l y not documented on the CRF or repor ted to the sponsor and IRB due to the study staf f a t tempt i ng to contac t the sub j ec t to se t up the 24 month fo l l ow-up v i s i t. In accordance w i th the protoco l, th i s event shou l d have been repor ted to sponsor and IRB w i th i n 24 hours of you becomi ng aware of th i s event. Your response i s i ncomp l e te ; i t does not i nc l ude a p l an to ensure proper repor t i n`~ of ser i ous adverse events. P l ease prov i de cop i es of po l i c i es and procedures. w i th expec ted comp l e t i on da tes, tha t are be i ng deve l oped and i mp l emented to ensure repor t i n(u) of ser i ous adverse dev i ce e f fec ts are i n accordance w i th the i nvest i ga t i ona l p l an and IRB po l i cy. Fa i l ure to ma i nta i n i nvest i ga t i ona l records for a per i od of two years a f ter the l a t ter of the da te on wh i ch the : i nvest i ga t i on i s termi na ted or comp l e ted or the da te the records are no l onger needed to suppor t a PMA [21 CFR (d) ] You fa i l ed to ma i nta i n records of Dup l ex F l ow Scans and Index Ext remi ty X-Ravs or F l uoroscopy for two years a f ter the study comp l e t i on. Examp l es of records not ava i l ab l c for a l l sub j ec ts enro l l ed i n t r i a l the are the fo l l ow i ng : 1) Dup l ex F l ow Scans a t d i scharge, 9 months, 24 months, and non-schedu l ed v i s i ts : and 2) Index Ext remi ty X-Rays or F l uoroscopy a t base l i ne, 9 month, and 24 month. In your response you state the records of the Dup l ex F l ow Scans and the Index Ext remi ty X-Rays for a l l sub j ec ts were not re ta i ned by the hosp i ta l. The or i g i na l s were sent to the ~, and the or i g i na l X-Rays were forwarded to th You a l so note you have contac ted the l abs to obta i n the or i g i na l s ancw i ~ l hvre ta i n. them w i th the study b i nders for a t l east two years. Your response i s i ncomp l e te. Al though you have requested the a forement i oned records, you do not i nd i ca te wha t po l i c i es and procedures, w i th expec ted comp l e t i on da tes, are be i ng deve l oped and i mp l emented to ensure proper ma i ntenance of study- re l a ted source records i n the future.

6 Page 6 Reyna l do F. Mu l i notapang, M.D. The above-descr i bed dev i a t i ons are not i ntended to be an a l l - i nc l us i ve l i st of de f i c i enc i es tha t may ex i st i n th i s c l i n i ca l study. I t i s your respons i b i l i ty as a c l i n i ca l i nvest i ga tor to assure adherence to each requ i rement of the Ac t and a l l app l i cab l e federa l regu l a t i ons. W i th i n 15 work i ng days a f ter rece i v i ng th i s l e t ter p l ease prov i de wr i t ten documentat i on of the add i t i ona l, spec i f i c steps you have taken or w i l l take to cor rec t these v i o l a t i ons and prevent the recur rence o i l - s i mi l ar v i o l a t i ons i n cur rent and future stud i es. Any submi t ted cor rec t i ve ac t i on p l an must i nc l ude pro j ec ted comp l e t i on da tes for each ac t i on to be accomp l i shed. Fa i l ure to respond to th i s l e t ter and take appropr i a te cor rec t i ve act i on cou l d resu l t i n the FDA tak i ng regu l a tory ac t i on w i thout fur ther not i ce to you. In add i t i on, FDA cou l d i n i t : i a te d i squa l i f i ca t i on proceed i ngs i n accordance w i th 21 CFR Send your response to : Food and Drug Admi n i st ra t i on, Center for Dev i ces and Rad i o l og i ca l Hea l th, Of f i ce of Comp l i ance, D i v i s i on of Bioresearch Mon i tor i ng, Spec i a l Invest i ga t i ons Branch, HFZ 311, 9200 Corpora te Road, Rockv i l l e, Mary l and 20850, At tent i on : Doreen Kezer, Ch i e f, Spec i a l Invest i ga t i ons Branch. We are send i ng a copy of th i s l e t ter to FDA' s F l or i da D i st r i c t Of f i ce and request tha t you a l so send a copy of your response to tha t of f i ce a t 555 W i nder l ey P l ace, Su i te 200. Ma i t l and, FL, I f you have any quest i ons, p l ease contac t Ms. Kezer by phone a t j T i rh D i rec t6r Of f i ce of Comp l i ance Center for Dev i ces and Rad i o l og i ca l Hea l th cc