- _ I NOTICE OF INITIATION OF DISQUALIFICATION PROCEEDINGS AND OPPORTUNITY TO EXPLAIN (NIDPOE)

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1 ~, ascxvrcr f, e 3 0 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 Rockv i l l e, MD NOTICE OF INITIATION OF DISQUALIFICATION PROCEEDINGS AND OPPORTUNITY TO EXPLAIN (NIDPOE) CERTIFIED MAIL - RESTRICTED DELIVERY RETURN RECEIPT REQUESTED Stephen D. Rossner, M.D. 97 Barnes Road Wa l l i ngford, CT Dear Dr. Rossner : Be tween March 4 and 10, 2005, Ms. Pa t r i c i a Murphy and Ms. M i che l l e Noe, represent i ng the Food and Drug Admi n i st ra t i on (FDA), conduc ted an i nvest i ga t i on and me t w i th you to rev i ew your conduc t of the fo l l ow i ng c l i n i ca l i nvest i ga t i on : Protoco l L ]ent i t l ed, "Ef fec ts of Blood Pressure Reduc t i on on H i gh Sens i t i v i ty_c-reac t i ve Prote i n (hscrp) : A Mu l t i center, Randomi zed, Open-Labe l, 2- Arm Para l l e l Group to Eva l ua te the Ef f i cacy of Modera te vs. Aggress i ve Ant i hyper tens i ve Therapy w i thl JandC ] to Reduce Blood Pressure and P l asma hscrp l eve l s. i n Pa t i ents w i th Stage 2 Hyper tens i on. " Th i s study of the i nvest i ga t i ona l drug L. 1was conduc ted by you for - _ I Th i s i nspec t i on i s a par t of the FDA' s Bioresearch Mon i tor i ng Program, wh i ch i nc l udes i nspec t i ons des i gned to eva l ua te the conduc t of research and to ensure tha t the r i ghts, sa fety, and we l fare of the human sub j ec ts par t i c i pa t i ng i n c l i n i ca l research have been protec ted. We are aware tha t a t the conc l us i on of the i nspec t i on, Ms. Murphy and Ms. Noe presented and d i scussed w i th you Form FDA 483. We have eva l ua ted the i nspec t i on repor t, the documents submi t ted w i th the repor t, other per t i nent i nforma t i on obta i ned by the Agency, and your March 23, 2005 wr i t ten response to the Form FDA 483, addressed to the D i st r i c t Of f i ce D i rec tor, Ms. Ga i l Coste l l o. Based on our eva l ua t i on of th i s i nforma t i on, FDA' s Center for Drug Eva l ua t i on and Research ( the Center ) be l i eves tha t you have repea ted l y or de l i bera te l y v i o l a ted federa l regu l a t i ons govern i ng the conduc t of c l i n i ca l stud i es i nvo l v i ng i nvest i ga t i ona l new drugs and the protec t i on of human sub j ec ts under T i t l e 21, Code of Federa l Regu l a t i ons (CFR), Par ts

2 Page 2- -Dr. Rossner 312 and Par t 50 (copy enc l osed), and tha t you submi t ted fa l se i nforma t i on i n a requ i red repor t to the sponsor. Th i s l e t ter prov i des you w i th wr i t ten not i ce of the ma t ters under comp l a i nt and i n i t i a tes an admi n i st ra t i ve proceed i ng, descr i bed be l ow, to de termi ne whe ther you shou l d be d i squa l i f i ed f rom rece i v i ng i nvest i ga t i ona l drugs as se t for th under 21 CFR A l i st i ng of the ma j or v i o l a t i ons fo l l ows. The app l i cab l e prov i s i ons of the CFR are c i ted for each v i o l a t i on. 1. You submi t ted fa l se i nforma t i on to the sponsor i n a requ i red repor t [21 CFR (a) ]. a. b. You fa l s i f i ed i nformed consent documents and case repor t forms (CRFs) to i nd i ca te tha t sub j ec ts had prov i ded wr i t ten i nformed consent when sub j ec ts had not prov i ded such consent. In an a f f i dav i t comp l e ted by you dur i ng FDA' s i nspec t i on (da ted March 8, 2005), you admi t ted tha t sub j ec ts 001, 002, and 004 had not s i gned the i nformed consent documents and tha t you had s i gned these sub j ec ts ' names on the i nformed consent documents some t i me a f ter the sub j ec ts were enro l l ed i n the study ( i. e., tha t the sub j ec ts had not prov i ded wr i t ten i nformed consent ). In add i t i on, on the Vi s i t 1/Day 0 Inc l us i on/exc l us i on CRF tha t you submi t ted to the sponsor, you checked the box marked " yes " to i nd i ca te tha t sub j ec ts 001, 002, and 004 hadprov i ded wr i t ten i nformed consent to par t i c i pa te i n the study. The protoco l requ i red tha t the sub j ec ts be randomi zed to rece i ve e i therc 160 mg da i l y or J 160/12.5 mg da i l y for 2 weeks, and a f ter 2 weeks those rece i v i ng[_ were to have the i r dose i ncreased to 320 m and those rece i v i ngc were to have the i r dose i ncreased to[ ~320/12.5 mg for a dura t i on of 4 weeks. As descr i bed i n grea ter de ta i l be l ow, you fa l s i f i ed CRFs to i nd i ca te tha t sub j ec ts were randomi zed to rece i ve study drug i n accordance w i th these protoco l requ i rements, when i n fac t these sub j ec ts were admi n i stered study drug i n a manner i ncons i stent w i th these requ i rements. In an a f f i dav i t comp l e ted by you dur i ng the i nspec t i on, you admi t ted tha t sub j ec ts d i d not a l ways take the protoco l - requ i red dose and tha t, i n some cases, you spec i f i ca l l y i nst ruc ted sub j ec ts to take hal f the protoco l - requ i red dose. The fo l l ow i ng CRFs were submi t ted to the sponsor : i ) i i ) The Vi s i t 1/Day 0 CRF i nd i ca tes tha t sub j ec t 001 was randomi zed to rece i ve 160/12.5 mg and the Vi s i t 2/Week 2 and Vi s i t 3/week 6 CRFs i nd i ca te tha t the sub j ec t ' s dose was i ncreased to L '320/12.5 mg for the requ i red 4 week per i od. However, source med i ca l records i nd i ca te tha t the sub j ec t was dosed w i th[ J 80 mg and[ ]25 mg da i l y a t study v i s i t 1 and the dose of [ ' was i ncreased to 160 mg a t study v i s i t 2. The Vi s i t 1/Day 0 CRF i nd i ca tes tha t sub j ec t 002 was randomi zed to rece i ve J160 mg and the Vi s i t 2/Week 2 and Vi s i t 3/week 6 CRFs i nd i ca te tha t

3 Page 3- -Dr. Rossner the sub j ec t ' s dose was i ncreased to[ 1320 mg for the requ i red 4 week per i od. However, source med i ca l records i nd i ca te tha t the sub j ec t was dosed w i th[ ]80 mg and[ ]12.5 mg da i l y a t study v i s i t 1. There i s no documentat i on i n source records to i nd i ca te tha t th i s dose was changed a t any t i me dur i ng the study. i i i ) The Vi s i t 1/Day 0 CRT i nd i ca tes tha t sub j ec t C )was randomi zed to rece i ve 1160 mg and the Vi s i t 2/Week 2 and Vi s i t 3/Week 6 CRFs i nd i ca te tha t the sub j ec t ' s dose was i ncreased to 320 mg for the requ i red 4 week per i od. However, source med i ca l records i nd i ca te tha t the sub j ec t was dosed w i th J 80/12.5 mg da i l y a t study v i s i t 1. There i s no documentat i on i n source records to i nd i ca te tha t th i s dose was changed a t any t i me dur i ng the study. c. To be enro l l ed i n the study, the protoco l requ i red tha t study sub j ec ts mee t the protoco l -spec i f i ed cr i ter i a for hyper tens i on- - the mean of three (3) repea ted sea ted ' measurements of systo l i c b l ood pressure of 160 to 185 mm Hg, i nc l us i ve, and/or d i asto l i c b l ood pressure of 100 to 109 mm Hg, i nc l us i ve. As descr i bed i n grea ter de ta i l be l ow, there were d i screpanc i es be tween the b l ood pressure read i ngs recorded i n the CRFs and the source med i ca l records a t Vi s i t 1 for sub j ec ts 001, 002, 003, and 004. In an a f f i dav i t comp l e ted by you dur i ng the i nspec t i on, you admi t ted tha t you recorded fa l se b l ood pressure read i ngs i n the v i s i t 1 CRFs so tha t sub j ec ts 001, 002, 003, and 004 wou l d appear to mee t the i nc l us i on cr i ter i on for hyper tens i on. The fo l l ow i ng CRFs were submi t ted to the sponsor : i ) In the Vi s i t 1/Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 001, da ted 6/8/04, you recorded b l ood pressure read i ngs of 168/102 mi n Hg, 166/100 mm Hg, and 166/102 mm Hg and you checked the box marked " yes " to i nd i ca te tha t the sub j ec t me t the cr i ter i a for hyper tens i on as de f i ned by the protoco l. However, source med i ca l records for sub j ec t 001 for tha t same da te recorded a b l ood pressure read i ng of 150/80 mm Hg. i i ) In the Vi s i t 1/Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 002, da ted 6/9/04, you recorded b l ood pressure read i ngs of 174/100 mm Hg, 170/100 mm Hg, and 170/100 mm Hg and you checked the box marked " yes " to i nd i ca te tha t the sub j ec t me t the cr i ter i a for hyper tens i on as de f i ned by the protoco l. However, source med i ca l records for sub j ec t 002 for tha t same da te recorded a b l ood pressure read i ng of 140/80 mm Hg. i i i ) In the Vi s i t 1/Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 003, da ted 6/9/04, you recorded b l ood pressure read i ngs of 164/102 mm Hg, 160/102 mm Hg, and 164/100 mm Hg and you checked the box marked " yes " to i nd i ca te tha t the sub j ec t me t the cr i ter i a for hyper tens i on as de f i ned by the protoco l. However, source med i ca l records for sub j ec t 003 for tha t same da te recorded a b l ood pressure read i ng of 142/80mm Hg.

4 Page 4- -Dr. Rossner i v) In the Vi s i t 1/Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 004, da ted 6/10/04, you recorded b l ood pressure read i ngs of 168/98 nun Hg, 164/100 mm Hg, and 164/100 mm Hg and you checked the box marked " yes " to i nd i ca te tha t the sub j ec t me t the cr i ter i a for hyper tens i on as de f i ned by the protoco l. However, source med i ca l records for sub j ec t 004 for tha t same da te recorded a b l ood pressure read i ng of 118/80 mm Hg. d. The protoco l requ i red tha t sub j ec ts who were onpharmaco l og i c ant i hyper tens i ve therapy w i th ang i otens i n conver t i ng enzyme (ACE) i nh i b i tors, ang i otens i n receptor b l ockers, a l dosterone b l ockers, or th i az i de d i ure t i cs (herea f ter "proh i b i ted ant i hyper tens i ve therapy " ) w i th i n 3 months pr i or to v i s i t 1 be exc l uded f rom the study. As descr i bed i n grea ter de ta i l be l ow, i n CRFs for sub j ec ts 001, 003, and 004 you i nd i ca ted tha t the sub j ec ts had not taken proh i b i ted ant i hyper tens i ve therapy dur i ng the 3 months pr i or to enro l l ment i n the study when source documents i nd i ca ted tha t sub j ec ts had been tak i ng proh i b i ted ant i hyper tens i ve therapy. In an a f f i dav i t comp l e ted by you dur i ng the i nspec t i on, you admi t ted tha t there were d i screpanc i es be tween CRFs and source med i ca l records concern i ng sub j ec ts ' past med i ca l h i stor i es and tha t cer ta i n sub j ec ts d i d not mee t the i nc l us i on cr i ter i a because they were cont ro l l ed on ant i hyper tens i ve med i ca t i on pr i or to enro l l ment. The fo l l ow i ng CRFs were submi t ted to the sponsor : i ) In the Vi s i t 1 /Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 001, da ted 6/8/04, you checked the box marked "no" to i nd i ca te tha t the sub j ec t had not rece i ved proh i b i ted ant i hyper tens i ve therapy i n the 3 months pr i or to tha t da te. However ; source records for sub j ec t 001 da ted 4/26/04 i nd i ca te tha t the sub j ec t was on Ben i car (o l mesar tan medoxomi l ), an ang i otens i n receptor b l ocker, and hydroch l oroth i az i de, a th i az i de d i ure t i c. Records da ted 5/4/04 i nd i ca te tha t Ben i car was d i scont i nued on tha t da te, but th i s occur red we l l w i th i n the 3 month w i ndow. i i ) In the Vi s i t 1/Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 003, da ted 6/9/04, you checked the box marked "no" to i nd i ca te tha t the sub j ec t had not rece i ved proh i b i ted ant i hyper tens i ve therapy i n the 3 months pr i or to tha t da te. However, source records for sub j ec t 003 da ted 4/28/04 i nd i ca te tha t the sub j ec t was prescr i bed D i ovan, an ang i otens i n receptor b l ocker, on tha t da te. i i i ) In the Vi s i t l /Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 004, da ted 6/10/04, you checked the box marked "no" to i nd i ca te tha t the sub j ec t had not rece i ved proh i b i ted ant i hyper tens i ve therapy i n the 3 months pr i or to tha t da te. However, source records for sub j ec t 004 da ted 4/30/04 i nd i ca te tha t the sub j ec t was prescr i bed D i ovan, an ang i otens i n receptor b l ocker, on tha t da te. e. The protoco l requ i red tha t potent i a l sub j ec ts be exc l uded f rom the study i f cer ta i n l abora tory parame ters were outs i de the ranges spec i f i ed i n the protoco l i n the 3

5 Page 5- -Dr. Rossner months pr i or to v i s i t enro l l ment, i nc l ud i ng serum crea t i n i ne >2.Omg/dL and any serum AST or ALT e l eva t i on tha t i s tw i ce the upper l i mi t of norma l. As descr i bed i n grea ter de ta i l be l ow, our i nvest i ga t i on found tha t you d i d not obta i n a l l of the requ i red l abora tory va l ues for sub j ec ts enro l l ed i n the study. In an a f f i dav i t comp l e ted by you dur i ng the i nspec t i on, you admi t ted tha t you recorded fa l se i nforma t i on on the case repor t forms for sub j ec ts 001, 002, 003, and 004 to i nd i ca te tha t the cer ta i n l abora tory resu l ts me t e l i g i b i l i ty cr i ter i a when the requ i red l abora tory eva l ua t i ons had not been done. The fo l l ow i ng CRFs were submi t ted to the sponsor : i ) In the Vi s i t l /Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 001, da ted 6/8/04, you checked the box marked "no" to i nd i ca te tha t the sub j ec t ' s l abora tory va l ues for serum AST and ALT were not outs i de the spec i f i ed ranges. However, a l abora tory repor t for sub j ec t 001 da ted 4/15/04 i nd i ca tes tha t serum AST and ALT test i ng was not done. There i s no other docurnentat i on of l abora tory test i ng hav i ng been donedur i ng the 3 month per i od pr i or to the sub j ec t ' s enro l l ment. i i ) In the Vi s i t l /Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 002, da ted 6/9/04, you checked the boxes marked ' no" to i nd i ca te tha t the sub j ec t ' s l abora tory va l ues for serum crea t i n i ne and serum AST and ALT were not outs i de the spec i f i ed ranges. However, a l abora tory repor t for sub j ec t 002 da ted 6/9/04 i nd i ca tes tha t serum crea t i n i ne and serum AST and ALT test i ng were not done. There i s no other documentat i on of l abora tory test i ng hav i ng been done dur i ng the 3 month per i od pr i or to the sub j ec t ' s enro l l ment. i i i ) In the Vi s i t l /Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 003, da ted 6/9/04, you checked the box marked "no" to i nd i ca te tha t the sub j ec t ' s l abora tory va l ues for serum AST and ALT were not outs i de the spec i f i ed ranges. However, a l abora tory repor t for sub j ec t 003 da ted 6/9/04 i nd i ca tes tha t serum AST and ALT test i ng was not done. There i s no other documentat i on of l abora tory test i ng hav i ng been done dur i ng the 3 month per i od pr i or to the sub j ec t ' s enro l l ment. i v) In the Vi s i t l /Day 0 Inc l us i on/exc l us i on CRF for sub j ec t 004, da ted 6/10/04, you checked the box marked "no" to i nd i ca te tha t the sub j ec t ' s l abora tory va l ues for serum AST and ALT were not outs i de the spec i f i ed ranges. However, a l abora tory repor t for sub j ec t 004 da ted 6/10/04 i nd i ca tes tha t serum AST and ALT test i ng was not done. There i s no other documentat i on of l abora tory test i ng hav i ng been done dur i ng the 3 month per i od pr i or to the sub j ec t ' s enro l l ment.

6 Page 6- -Dr. Rossner 2. You fa i l ed to obta i n the l ega l l y e f fec t i ve i nformed consent of sub j ec ts par t i c i pa t i ng i n the study [21 CFR 50.20, 50.27, and ]. An i nvest i ga tor i s respons i b l e for obta i n i ng the i nformed consent of each human sub j ec t to whom study drug i s admi n i stered i n accordance w i th the requ i rements of 21 CFR Par t 50 (see 21 CFR ). In par t i cu l ar, i nformed consent i s requ i red to be documented by use of a wr i t ten consent formed approved by an IRB 1 and s i gned and da ted by the sub j ec t or the sub j ec t ' s l ega l l y author i zed representat i ve a t the t i me of consent (21 CFR 50.27(a) ). Our i nvest i ga t i on found tha t, for sub j ec ts 001, 002, and 004, you d i d not document the i r i nformed consent by the use of a wr i t ten consent form s i gned and da ted by the sub j ec ts. Fur thermore, i n an a f f i dav i t comp l e ted by you dur i ng the i nspec t i on, you stated tha t you " verba l l y to l d the sub j ec ts about the study, " and admi t ted tha t you s i gned these sub j ec ts ' names on the i nformed consent documents some t i me a f ter the sub j ec ts had been enro l l ed i n the study. There fore, you d i d not obta i n the l ega l l y e f fec t i ve i nformed consent of sub j ec ts 001, 002, and You fa i l ed to ensure the stud i es were conduc ted accord i ng to the i nvest i ga t i ona l p l an [21 CFR ). a. The protoco l re u i red tha t the sub j ec ts be randomi zed to rece i ve e i ther t ~ 160 mg da i l y or ]160/12.5 mg da i l y for 2 weeks, and a f ter 2 weeks those rece i v i ng t to have the i r dose i ncreased to 320 m and those rece i v i ngl A were to have the i r dose i ncreased to~ 1320/12.5 mg for a dura t i on of 4 weeks. Sub j ec ts 001, 002, and 003 were not dosed i n accordance w i th the protoco l. (See v i o l a t i ons # l.b. i - i i i above. ) b. c. The protoco l requ i red tha t sub j ec ts mee t the protoco l -spec i f i ed cr i ter i a for hyper tens i on to be enro l l ed i n the study- - the mean of three (3) repea ted sea ted measurements of systo l i c b l ood pressure of 160 to 185 mm Hg, i nc l us i ve, and/or d i asto l i c b l ood pressure of 100 to 109 nun Hg, i nc l us i ve. Sub j ec ts 001, 002, 003, and 004 d i d not mee t the cr i ter i a for hyper tens i on spec i f i ed i n the protoco l, but were none the l ess enro l l ed i n the study. (See v i o l a t i ons # l. c. i - i v above. ) The protoco l exc l uded sub j ec ts who were on pharmaco l og i c ant i hyper tens i ve therapy w i th ang i otens i n conver t i ng enzyme (ACE) i nh i b i tors, ang i otens i n receptor b l ockers, a l dosterone b l ockers, or th i az i de d i ure t i cs wi th i n 3 months pr i or to v i s i t 1. Sub j ec ts 001, 003, and 004 were tak i ng proh i b i ted ant i hyper tens i ve therap i es w i th i n the 3 month per i od pr i or to v i s i t 1, but were none the l ess enro l l ed i n the study. (See v i o l a t i ons # l.d. i - i i i above. ) 1 Wr i t ten consent i s requ i red un l ess an IRB de termi nes there i s a bas i s to wa i ve the requ i rement for consent. wr i t ten To wa i ve the requ i rement an IRB must de termi ne tha t the study presents no more than r i sk mi n i ma l or the study mee ts the requ i rements for an except i on f rom i nform consent for emergency research CFR (c)Ne i ther except i on app l i es to Protoco l

7 Page 7- -Dr. Rossner d. The protoco l exc l uded sub j ec ts i f cer ta i n l abora tory parame ters were outs i de the protoco l -spec i f i ed ranges i n the 3 months pr i or to v i s i t 1, i nc l ud i ng serum crea t i n i ne >2.Omg/dL and any serum AST or ALT e l eva t i on tha t i s tw i ce the upper l i mi t of norma l. In an a f f i dav i t comp l e ted by you dur i ng the i nspec t i on, you acknow l edged tha t you d i d not obta i n resu l ts of cer ta i n requ i red l abora tory test i ng (serum crea t i n i ne and/or serum AST and ALT) a t study v i s i t 1, or w i th i n the 3 months pr i or to study v i s i t 1, for sub j ec ts 001, 002, 003, and 004. These sub j ec ts were none the l ess enro l l ed i n the study. (See v i o l a t i ons # l. e. i - i v above. ) 4. You fa i l ed to ma i nta i n adequa te and accura te case h i stor i es tha t record a l l observa t i ons and other da ta per t i nent to the i nvest i ga t i on on each sub j ec t [21 CFR (b) ]. a. The protoco l spec i f i ed tha t a l l concomi tant med i ca t i ons must be recorded on the Concomi tant Med i ca t i on/s i gn i f i cant Non-Drug Therap i es CRF. Our i nvest i ga t i on found tha t sub j ec ts 001, 002, 003, and 004 were tak i ng concomi tant med i ca t i ons dur i ng the study, but these med i ca t i ons were not recorded i n the appropr i a te CRFs. In an a f f i dav i t comp l e ted by you dur i ng the i nspec t i on, you acknow l edged tha t i nforma t i on on concomi tant med i ca t i ons recorded i n the CRFs d i d not a l ways ma tch i nforma t i on recorded i n source med i ca l records. For examp l e : i ) i i ) Source med i ca l records i nd i ca te tha t sub j ec t 001 was tak i ng Lopressor 25 mg da i l y dur i ng the study, but th i s i nforma t i on was not recorded i n the CRF. Source med i ca l records i nd i ca te tha t sub j ec t 002 was tak i ng L i p i tor dur i ng the study, but th i s i nforma t i on was not recorded i n the CRF. i i i ) Source med i ca l records i nd i ca te tha t sub j ec t 003 was tak i ng L i p i tor, and asp i r i n dur i ng the study, but th i s i nforma t i on was not recorded i n the CRF. i v) Source med i ca l records i nd i ca te tha t sub j ec t 004 was tak i ng Hyt r i n, Norvasc, hydroch l oroth i az i de, asp i r i n, and l ovastat i n dur i ng the study, but th i s i nforma t i on was not recorded i n the CRF. b. The protoco l requ i red tha t adverse events be recorded i n the Adverse Event CRF. The protoco l de f i nes " adverse event " as any undes i rab l e s i gn, symptom or med i ca l cond i t i on occur r i ng a f ter star t i ng study drug. Accord i ng to source med i ca l record for sub j ec t 001, the sub j ec t exper i enced d i zz i ness wh i l e on study med i ca t i on, but th i s adverse event was not recorded i n the Adverse Event CRF. c. Our i nvest i ga t i on found tha t the i n i t i a l s of four sub j ec ts enro l l ed i n the study were i naccura te. You recorded the fo l l ow i ng i n i t i a l s i n study documents (e.g., case repor t forms and i nformed consent documents) for the sub ' ec ts who were enro l l ed i n the study : 001 L J 002L ~003L ~and 004 J Dur i ng the i nspec t i on, you admi t ted tha t you enro l l ed sub j ec ts under d i f ferent i n i t i a l s and tha t

8 Page 8- -Dr. Rossner the cor rec t i n i t i a l s were those conta i ned i n the med i ca l records. The i n i t i a l s recorded i n the med i ca l records were as fo l l ows : 001 C 1002L ]003 ]and 004[ Th i s l e t ter i s not i ntended to be ana l l - i nc l us i ve l i st of de f i c i enc i es w i th your c l i n i ca l stud i es of i nvest i ga t i ona l produc ts. I t i s your respons i b i l i ty to ensure adherence to each requ i rement of the l aw and re l evant regu l a t i ons. On the bas i s of the above l i sted v i o l a t i ons, the Center asser ts tha t you have repea ted l y or de l i bera te l y fa i l ed to comp l y w i th the c i ted regu l a t i ons and submi t ted fa l se i nforma t i on to the sponsor i n a requ i red repor t. Your ac t i ons have exposed human sub j ec ts to unnecessary r i sks and j eopard i zed the i ntegr i ty of da ta. The Center proposes tha t you be d i squa l i f i ed as a cl i n i ca l i nvest i ga tor. You may rep l y to the above stated i ssues, i nc l ud i ng an exp l ana t i on of why you shou l d rema i n e l i g i b l e to rece i ve i nvest i ga t i ona l produc ts and not be d i squa l i f i ed as a c l i n i ca l i nvest i ga tor, i n a wr i t ten response or a t an i nforma l conference i n my of f i ce. Th i s procedure i s prov i ded for by regu l a t i on 21 CFR W i th i n f i f teen (15) days of rece i pt of th i s l e t ter, wr i te or ca l l me a t (301) to ar range a conference t i me or to i nd i ca te your i ntent to respond i n wr i t i ng. Shou l d you choose to respond i n wr i t i ng, your wr i t ten response must be forwarded w i th i n th i r ty (30) days of rece i pt of th i s l e t ter. Your rep l y shou l d be sent to : Joseph Sa l ewsk i D i rec tor (Ac t i ng) D i v i s i on of Sc i ent i f i c Invest i ga t i ons, HFD-45 Of f i ce of Med i ca l Po l i cy Center for Drug Eva l ua t i on and Research ' Food and Drug Admi n i st ra t i on 7520 Stand i sh P l ace, Room # 103 Rockv i l l e, Mary l and Shou l d you request an i nforma l conference, we ask tha t you prov i de us w i th a fu l l and comp l e te exp l ana t i on of the above l i sted v i o l a t i ons. You shou l d br i ng w i th you a l l per t i nent documents, and a representat i ve of your cho i ce may accompany you. Al though the conference i s i nforma l, a t ranscr i pt of the conference w i l l be prepared. I f you choose to proceed i n th i s manner, we p l an to ho l d such a conference w i th i n 30 days of your request. At any t i me dur i ng th i s admi n i st ra t i ve process, you may enter i nto a consent agreement w i th FDA regard i ng your future use of i nvest i ga t i ona l produc ts. Such an agreement wou l d termi na te th i s d i squa l i f i ca t i on proceed i ng. Enc l osed you w i l l f i nd a proposed agreement be tween you and the FDA.

9 Page 9- -Dr. Rossner The Center w i l l care fu l l y cons i der any ora l or wr i t ten response. I f your exp l ana t i on i s accepted by the Center, the d i squa l i f i ca t i on process w i l l be termi na ted. I f your wr i t ten or ora l responses to our a l l ega t i ons are unsa t i sfac tory, or we cannot come to terms on a consent agreement, or you do not respond to th i s not i ce, you w i l l be of fered a regu l a tory hear i ng be fore FDA, pursuant to 21 CFR 16 (enc l osed) and 21 CFR Be fore such a hear i ng, FDA w i l l prov i de you not i ce of the ma t ters to be cons i dered, i nc l ud i ng a comprehens i ve statement of the bas i s for the dec i s i on or ac t i on taken or proposed, and a genera l summary of the i nforma t i on tha t w i l l be presented by FDA i n suppor t of the dec i s i on or ac t i on. A pres i d i ng of f i cer f ree f rom b i as or pre j ud i ce and who has not par t i c i pa ted i n th i s ma t ter w i l l conduc t the hear i ng. Such a hear i ng w i l l de termi ne whe ther or not you w i l l rema i n ent i t l ed to rece i ve i nvest i ga t i ona l produc ts. You shou l d be aware tha t ne i ther ent ry i nto a consent agreement nor pursu i t of a hear i ng prec l udes the poss i b i l i ty of a coro l l ary j ud i c i a l proceed i ng or admi n i st ra t i ve remedy concern i ng these v i o l a t i ons. S i ncere l y yours, {See appended e l ec t ron i c s i gna ture page } Joseph Sa l ewsk i D i rec tor (Ac t i ng) D i v i s i on of Sc i ent i f i c Invest i ga t i ons, HFD-45 Of f i ce of Med i ca l Po l i cy Center for Drug Eva l ua t i on and Research Enc l osures : CFR CFR Consent Agreement

10 g ned e l ec t ron i ca l l y and Th i s i s a representat i on of an e l ec t ron i c record tha t was s i th i s page i s the man i festat i on of the e l ec t ron i c s i gna ture / s / Joseph Sa l ewsk i 5/10/ :46 :00 PM