FDA safeguard kits for treatment of prostate cancer that use bone wax

World Wide Medical Technologies CITIZEN PETITION February l&2005 Dockets Management Branch Food and Drug Admiktmtion Department of Health and Human Services Fh. l-23 12420 Parklam Dr. Rc&de,MD 20857 Re: . Citizen Petition U&g FDAto SW the public From Gxnmerual Brnctrythe -wethe that Use NonorbableBone Wax or&n-Absorbable ReformulatedaFaux Bone Waxn Needle Dear Sir or Madam: Overwhelmingscientificdatapublishedin journalsfmm the fields of orthopedic,mastoid, thoracic, canliac,foot, plastic,ophthalmk, and dentalsurgeryindicatesthat the migration of bone wax from swgical bone sitesinto areasof soft tissuewithin the body can potentiallyleadto seriouscomplications,in&ding the formation of cancerous tumors. Bone wax is a substance that was developedas a hemostasis agentfor use in bone, and,to the best of our knowledge,it has only been clearedby the Food and Drug Admirkmtion (TDAm), as a stand-alone pmduct, to stop bone bleedinglocally? Accodingly, we believethat the recentintroduction of commercialbrachytherapy for the kits tnzatmentof prostatecancer- ie, pre-plugged, pre-loadedneedles usedin brachy&eIzpy Oct. 24,1997(chning “subd l Stp,eg, United States Suxgicai Gqo cation,510(k)No. K971680, with Johnson&Johnson’ EthicoP (pmmendment)andLulms” BoneWax (K791405)) s 0; Inc., 510(k)No. K024372, June 19,2003(&Q. equivabzxd CP Medical, February 18,2005 Page 2 treatment- that useoff-label non-absorbable bone wax or reformulated“faux bone wa~“~mises significantsafetyissues? ExecutiveS-q Alamingb, we believecompanies nxxnufm the radioactive“seeds” are usedin that that commercialbrachythempy and the subcontmcto~who assemble kits, thesekits for them, have recentlybegunto market thesecommercialkits to hospitalsand physicians without giving appropriateconsidemion to the potentialdangersidentifiedin the scientificlitem. When used,thesekits permanentlyimplant a substantial amountof bone wax or refomulated “faux bone wax- into soft tissue,which accordingto the literaturecan potentiallycausea myriad of compl.ications, inc* l sarcomas (eg, angiosarcomas), 0 CIhrmic inflammtion (grmulomatisinfection), MAed foreign body reaction, Epistaxis, Allexgic Racti0ns, 0 0 0 0 a sigmoid thlmbosis, sinus Foreign body venousembolization, 2 Reformulated “faux boneum” &ers to a reform&ion of bonewsx that hasbeenusedasneedle plugs,andto thebestofourknowkdge,itisuntesmL Itisourunde~throughindependentlaboratorytesting,tbat traditionalbonewax hasbeenreformulated addingfibms substances rise the pmduct’ meltingpoint to by to s makeit lesssticky and more solid at highertemperatures. Jordi Letter,datedJuly 14,2003(Bg3). Se We can only opine &at certainman&ctums havedeveloped reformulated *faux bone4 because bonewax needle plugsproved to be unstable duringshipping. Companies we believemay sell brachyt.herapy containing that kits bonewax or reformulated “faux bonewax” includeMentor Corp.,Best Ivkdid, International Brachytherapy, (TV’ andBEBIG Isotopen-und S.A. ), Medizintechnik GmbH FBEBIG”). SeMiscellaneous Promotional Materialfor Kits UsingBoneWax or “Faux BoneWax* Plugs(BHg). 3 February 18,200s page3 0 Pulmonarycomplications, to migration to the lungs,and due Quadriplegia 0 Given that appnximately232,~O Americanmen axeexpected be diagnosed to with prostate cancerin 2005 alone,’ that appnximateiy40,000of those men will chooseto undergo and brachytheqytnzatment,5 commercialbrachytherqykits that usebone wax or nformulated “faux bone waxBposea massive public healththreat. The extent of this public healththrea& however,cannot yet be known, as it can take yearsfor complications manifest. to This massivepublic healththteat maybe averted,or at leastminimized,giventhat commercial bmhythel.apykits that useoff-label bone wax or reformulated“faux bone wax” needleplugs,to date,have likely only impacteda few thousandpatients. Accordingly,if the FDA actsquickly to removethe products from the mariret,at leastuntil the kits can be proven to be safe,substantial adversehealth eventsmaybe avoided ‘ llerefore, this petition is respe&ullysubmitted pursuantto 21 CFJL $10.30~to urge that the that Commissionerof the FIX (1) ban the use of commercialbrachytherapykits use nonabsorbable bone wax or reformulated“faux bone waxn needleplugs,under Section516(a)(l) of the FederalFood, Drug and CosmeticAct (“l?FDCA”), because presentan “umasonable they of such and substantialrisk of illnessor ir$.~$‘ QI-(2) at rnGmum, quire allmanuf-rs ~ commellcialbrachytherapykitsto obtain FDA approvalof a premarketapprovalapplication (“PMA”) pxior to commercialdistribution,which would force manufacturers affirmatively to Regaxlless whetherFDA decidesto ban bone of prove that such kits are safeand efficacious.8 wax or reformulated“faux bone wax”kits, or nquitz PMAs, FDA should also rescindany 4 Se eg, AmehcanCancer societyWebsite(esthat U2,OsO Americanmen will be diagnosed prostate with 5 Louis Potters,h4.D., and Cancer,malewe, 0. 6 21 C.F.R § 10.30(2004). 7 21 USC $36Of(a)(l)(Supp.2004). As explained herein,we do not believe the unreasonable substautial that and risk of illnessor injury could be correctedor ehinated by labehg modifiiations. 8 IAimbly, this CitizenPetitionody addresses commercial bmchytherapy ad is not intended affect kits to brachytherapy systems assembled medicalprofessionals to performingbrachythempy by prior surgery. February18,2005 page4 curnmt “substantialequhlence” ordersfor such kits and removefrom the market any bmchytherapykitscunentlymarketedin the absence 510(@clearance approval of or The aboveactionswould haveno adverse impact on prostatecancerpatientsas brachythempy kits containingbioabsorbable plugsor needles designed obviatethe use of plugs altogether to have aheadybeenclearedbythe agencyand am readilyavailable. A. . Backmmmd and Owmew Bra&therapy is an out-patientcancertreatmentthat is an accepted alternativeto generalsurgery. Ittvo~esplacinga~ofradioactivesourcesintothebodytodestroycancercells~low dosetxdiatbn. TheseIX&U&T soums, or “seeds,” placedinto the body usingmultiplehollow axe needles. lhese needles as holdersand can& of theseseeds act until the needles insertedinto ate predeterminedareas the body of Lkually, between15 and 60 needles usedin eachprocedum. Typically,in a hospital,a medical are physicistprepamsthe needles loadsthe seedsoumes spacers eachneedle rior to the and and into procedure. ‘ deliveryend of the needleis closedfor the fkst 2-5 mm with bone wax! to pment Ihe the iadioactiveseeds from dislodging fallingout prior to insertioninto the body or Priortoinse~~asolidwirestyletisc~~edintotheprorcimaendoft)aecannubto rest upon the stackof seeds spacers the deliverytip of the needle.The physician and at then inserts the needles one-byone into the patient,and once insertedinto the bodyto the proper position,the styletisheldfinnandthecannulaofthene~ismoved~~thep~~eradof~~ This motion depositsthe radioa&e seeds, spacers, the bonewax needle and plug into the body in a trackorlineasthecannulaispulledback,leavingtheseedstope~n~resideinthebodyasthe radioactive dosedecays the treatmenttint. over z . . Polimtlal Risks 0f .Commerrializiagthe Use of Bone Wm or RefoxnmlakQ “Faux BoneWax”m SoftTissue Although physicianshave used bone wax “off-label” in brachytherapy procedures,it is doubtful that reliableconclusionsregardingsafetycould be extrapolated from associated in that field data (to the extent that it exists)because migration of radioactiveseedsand/or bone wax plugs is the not routinely checkedbeyondthe initial “same day’chestx-ray and a subsequent day follow30 9S~SubirNag,~.,ct~,PldmxmyEm~~I~~P~lO3S~~Gwo’ narrt inthzI’ %ate, 39 Int. Journal of Radiatk Oncology Biol. Phys. 667 (1997) 0. February l&2005 %F5 up x-ray of the patient’ lungs. However, publishedstudies”show that seedmigration can occur s procedure (a full 3 months beyond the anywherefrom 1 to 127 days after the brachytherapy star&xl 30 day follow-up). Notably, we did not identify any studies,to date, that have focused on bone wax migration and the mid- to long-term effects of bone wax n&ding in soft tissues afterthe initial brachytherapypmcedum. Due to this lack of data on potential migmtion beyondthe typical bmchythempy followwp period, and associated complications, havegnwe concernsabout the safetyof commercial we brachythempykitsthat usenon-absorbable bone wax or reformulated“faux bone wax” off-label as needleplugs. Distuhingly, there is substantial scientificlitemtum on the negativeeffectsof the use of bone wax and its ensuingcomplicationsin other fields of medicalpmctice(cited and discussed detail in in Sectionc(l)(b)), indicating that bone wax doesmigrateto soft tissuesthtoughout the body and can cause&tonic infhmmation (gmnulomatis infection),markedforeign body reaction, sarcomas angiosarcomas), (eg, epistaxis, allergicnzwtions,sigmoidsinusthrombosis,foreign body venousembolization,and pulmonarycomplications.Moreover,it is believedthat bone wax left in the body has evencontributedto quadriplegia.” Further, multiple bmchytherapy oncologyarticleshavereportedthat seedmigration from the prostategland to the lungsis common, and someexpertsestimate it occursin l&36% of all that implant procedures.” Given this high incidence,and the fact that the bone wax or reformulated “faux bone wax* plug necessarilyn&lesin front of the line of seeds within eachneedle,it is reasonable concludethat the bone wax plug may alsocommonlymigrateto the lungs. to Given the history of bone wax complications arisingfrom its inadvertentdisplacement soft into tissue,it is even more disconcerting certainmanufacturers that haveintroducedto the market commercialbracbythemapy that use plugsformed from what is, to the best of our knowledge, kits an untestedreformulation of bone wax. We can only opine that the manufacturers kits with of bone wax plugs madethe switch to thesereformulated“faux bone wax”plugsbecause bone the wax plugs previouslyusedproved to be temperature unstableduring shipping. It is our undermanding thesemanufmrs developed reformulated“faux bone wax” by that the reformulatingthe compoundsin traditional bone wax and addingfibrous substances tie the to ‘ OSee,eg,SubL:NakUD.,etal,PIPImxrnyE~nP~I~~P~~O3SaaklSr Grraim# in &I+maie, 39 lnt. Journalof RadiatbnOncologyBiol. Phys.667(1997)0. I1See& discussion Sectionc(l)(b). at ** SL41 discussion Sectionc(l)(b). irls#, at February18,200s Page6 pmduct’ melting point and to makethe product lesssticky and more solid at higher s temperntureS. Reformulated“faux bone wax,”at nitkmuq posesthe samesafetyhazadsas bone wax because, like bone wiq it is non-absorbable.Iherefore, like bone m it may migrateto undesirable locationsin the body, where it can lodgepermanently causeadverse and events. Moreover, we undersMndthat reformulated“faux bone wax” is specifically formulatedto main&its format highertemperatures, thus, it is likelyto main&n its format bodytempe~s. and Because is it more solid and lessstickythan traditionalbone wax at bodytempe~~~~~s, reformulated“faux bone wax” should be evenmore likely than bone wax to m&ate independently from the seeds. Reformulated“faux bone wax” alsocould poseadditionalsafetyhazardsbecause, our to knowledge,its new chemicalformula(s)hasnot beenclinicallytested, it doesnot have a and histoxyofanytypeofuseinthebody? 2. auestedActions bv the FDA . Accordingly,we believecommercialbrachytherapykits usebone wax or reformulated“faux that bone wax” needleplugspresentan “unreasonable substantial of illnessor injury,” such and risk that FDA should take immediateaction to ban the devicesunder Section516(a)(l) of the FFDCA.” Patientswould continueto haveaccess comme~ial brachytherapykitsthat do not to useplugs at all, or use syntheticbioabso&xble~lugs.~ Imponantly, the materialusedin synthetic bioabsotile phgs, unlike bone wax or reformulated*faux bone wax,”is w&established as safefor use in soft tiw.~,‘ and therefore,doesnot posethe samerisks as bone wax or ~ refoxmulated“faux bone wax.” At rninimq FDAshould requiremanuf~rs of commercialbt’ dchythempykits use bone that wax or reformulated“faux bone wax”plugsto obtain PMA approvalprior to commercial distribution. Suchkits are new devicesthat raisecompletelydifferent issues fromother legally ma&ted devices. Thus, we believesuchkits shouldbe regulated classIII devices,and should as IW@E I?IW~approval~ l3 Se it& d.kcussion Sectionc(l)(b). at l4 21 U.S.C § 36Of(a)(l)(Supp.2004). 15 example, For Imagyn(succeeded Bard),Implaut Sciences, by IsoAid, Oncum,North American!kientifii and Theragenics, amongothers,all sellbrachytherapykits do not usebonewax or reformulated’ boneWaKo that faux needle plugs. &E Literaturefor BrachydxmpyKits W&out BoneWax or “Faux BoneWax* Plugs(&,J$. l6 See it#q at SectionC(2)(b). ‘ Stz21 US.C s 360e(Supp.2004). 7 February 18,2005 pase7 Indeed, we do not believesuch devicesare eligiblefor 5IO(@clearance all. The overwhehning at scientific data indicatingthat the use of bone wax or reformulated“faux bone wax” needlephgs in commercialbrachytheqykits is dangerous, and of itself, is evidence manufacttuzx~ in that cannot show that such kits are “substantiallyequivaknt” predicatedevices, requiredunder to as the 510(4 process.” If manufactu~rswere requiredto file PMAs, then theywould haveto prove that the devicein its entirety- in&ding all of the components,such as needlepb presentsa ureasonable assurance safety~19 the FFDCA nquites.20 of as In addition, regardless which approachFDA decides take, it should alsorescindany current of to for “substantialequivalence” orders (ie, 510(k) clearances) suchbrachytheqy kits - and xxmove fmm the market anybrachythezqykits currentlyma&ted in the absence SO(k) clearance of or PMA approval B. Actions Requested 1. FDA should immediately take actionto ban the saleof commercialbrachythempy kits that use bone wax or reformulated“faux bone wax” needleplugs;pi FDAshould immediatebrequiremanufactu~rsof commercialbrachytherapykits that usebone mu or reformulated“faux bone wax”needlephgs to obtain PMA approvalfor their kits, rather than 510(k)chance, prior to cornmercd distxibutio~and 2. Regadlessof whether FDA decides ban commercialbrachythexqykits that to usebone wax or reformulated“faux bone wax”phqs, or requirePMAs, FDA should also rescindanycun-ent“substantialequivalence” orders (k, 510(k) clearances) brachythexapy that usebone wax or reformulated“faux bone for kits n - and removefrom the marketanybzxhytheqykits cuxxentlymarketed in Eabsence of 510(k)clearance PMA appmvaL or ** Se21 u.s.c $§ 360(k),36oc(f),@ (Supp. 2004);21 CPR ~807.100(b) (2004); Premarket Notification 510(k): nts for MedicalDevices,HHS publicationFDA, 95-4158 (Aug. 1995). k&-Y~q~ 19 Section515(d)of the FFDCA tzquiresFDA to determine whethera devicehasa “reasonable assurance safety,” of (Supp. 2004). in decidingwhetherto grantor denya PMA. Set21 US.C $36Oe(d) 20 keeping In with FDA’ bkmpatibilityg s docume t, f or a PhiA, manufma n of brachytherapykits with bonewax or refordated “faux bonewax”plugsalsowould haveto demonstrate the bonewax wdd not that cause adveneeffects. SeRequiredBiocompatibiiTraining andToxico~Pdiles for Evaluationof Medical Devices(May 1,1995),hQzhww.f~ov/c~ . February 18,2005 Page8 C $aateantof GIlmlds 1. a. . . Stan&d to Ban Me&d Dewceq Section516(a)(l) of the FFIXA providesthat FDA may initiate proceedings promulgatea to qulation to ban a deviceif the device“presentssubstamial deceptionor an unreasonable and Ihe substantialrisk of illnessor injury’ that cannot be correctedby a labelingchange.2’ qplations implementingthat sectionstatethat, in determiningwhethera deviceposesa substamialrisk, the FDA must considerwhetherthe risk is “important, materialor sign&cant”in relationto the benefit from the deviceto the public health2 The mannerin which FDA has interpretedSection516(a)(l) of the FFDCA in the past is insmmive. In 1983,FDA bannedprosthetichair fibers, after determiningbasedon scientific litmam and reports of adverseevents,amongother things,that there were no conditionsunder which the devicescould be safeIymarkxed23Accordingto FDA, prosthetichair fibers nxt the standan!in Section516(a)(l) of the FFDCA because there could be: no benefit to the public heath from continuedmarketingof prosthetichair fibers, and the . . . risk posedby their continuedmatketingis important, mated, and significant,considering severityof the infections,illnesses, the or injuriescausedbytheir implantatior~*’ The injuriescaused the prosthetichair fibers were largelydue to foreign body reactions,and by they includedbreakage the fibers at the scalpline, permanentadditionallossof naturalhair, of itchiness,facial swelling,severepain, infections,severeand punctatescarring,and even long-term risk of developingcancer. Someof theseinjuriesevenrequiredcorrectivemedicalor surgical treatment. 21se?21u.s.c $36of(a)(l) (Sllpp. 2004). 22Se21 CF.R 5 89521(a)(l)(2004).FDA specificaUydeclined opportunityto an deft “unreasonable” it is used as in!ktion516(a)(l) oftheFFDCA,stadngthatthelegislativehistoryo~definedtheterm*substantial” SW++ Fed. Reg.29214,29215 @by l&1979). 2~Se48 Fed. Reg.25126,25127-28 (June3,1983). February l&2005 Page9 Notably, in that case,FDA specifically statedthat it did not haveor needany infomation regardingthe incidenceof the adverse eventsbecause riskof infection with pmthetic hair the fibers was inherent and the adverse eventswere sevens.=The fact that it did not needany information regardingincidenceis pa&&rly ixmru&ve,giventhatFDAwasjustifyinga“ban” with a “specialeffective date”and thereforehad to meet a higher legalstandanl,showingthat the risk posedbythe devicespresentedan %nreasonable, dinxt, and substantial dangerto the health of individllals.“26 b. BoneWax”NeedlePhes Meet the Lew for a Ban In this case,as with the pmthetic hair fibers, overwhelmingscientifii dataindicatesthat commellcial brachytherapykitsthat usebone wax or refomulated “faux bone wax” as needle plugs presentan “unreasonable substantial of illnessor injury.“*’ As detailedbelow, as and risk with prosthetichair fibers, the risk presented important, material,and s;gn;f;cant,given the is severityof the illnesses injuriesthat the devicescan cause.Moreover,aswith pros&tic hair and fibers, this risk cannot be avoidedthmugh labelingbecause risk is inherentwhen bone wax or the reformulated“faux bone wax* are usedoff-label as needleplugsin commercialbrachytheqy kits. Bone wax doesnot absorbinto the body? As a nmlt, bone wax usedduring medical procedureshas causedchronic inflammation(grmulomatisinfection), ma&d foreign body mction, smomas/angiosonras (ie, blood vessel cancer),epistaxis, allergicreactions,sigmoid sinusthmnbosis, and puhnonarycomplications, it hasevencomitmted to pamplegia and and quadriplegia.~Bone wax, like the prosthetichair fibers, is a foreign object in the body, and as *5&??if 26Sed Stzdo21 C.F.R.$895.30(2004)(regardin% special effectivedates). *’21 USC $36of(a)(l) (Supp.2004). 28Ole-Gu~ar,UD.aaL,CmpliartiarS~ao~UseaS~&rreWmcSetarP~,32~Journaof Ankle andFoot Sugery505 (1993)(aclmowle.dging bonewax is not absorbed) that (8Hs). 29~Gunnar,UD.aal,OxrpliambraSgmE#ydotheUse~S~&neW1ocinSaenPaa’ slr,32TheJournaof involvingfoot andshouldersugey, that bone Ankle andFoot Surgery505 (19q3)(concluding, as on sevencases b ed wax can cause chronic idbmmamn andforeignbody reaction) 0; James Au&o, DDS., & 4, Fonigd& n#diat tu kw wx, 58(l) Oral surgery, Oral hhdicine, Oral Pathology98 (1984)(concluding, based a casestudy on wherebonewax usedduringmoth surgerycaused chronichfhmathn, that “[wjhen bonewax is left in tissue,it stimulates elicits an infhmamryresponse anda fo+&odymction”) or (Att.; BlakeA Morrison,M.D., S& ?iwecf&acaani;6,16 BUMC Proceedings (2003)(The link between 285 foreignbodiesandsarcoma has Februaryl&2005 Page10 such uiggersthe body’ defensesystem,actingas a catalystfor many of thesecomplications, s such as granulomatous infections,epistaxis, alkgic nxctions, as well as sarcomas?0 and Importantly, thesesignificantadverseeventsare documented only by the litem, but alsoby FDA’ not s medicaldevicereponing (“MDR”) database, which containsa number of qxnts fmm manufmrs, importers, and user facilities~’ xlSa:eg;,Ole-Gunnar,~.etd,~S~&~UsedStodPdBaEW~inSaenP~,32~ Journalof Ankle andFoot Sugery505 (1993)(BHg); James AldiO,DDS.,etd,Faajgnbody&lobae~, 58(l) Oral Surgery, Oral Medicine,Oral Pathology98(1984)010); BlakeA Monison, M.D., S@ f&s=d de ech, 16 BUMC Pmceedings (2003)(Aa.; B;ryramoals, M.D. andOzkanUnal, M.D., I285 r+pd$+ atdkune um, 92 J. NeumsurgzSpine248(April 2000)(Att.; W.K. Low andCS. Sii BarpWm Fmign BaiyGrtmahzin~M~64ORL38(2002) (Att. RakeshB.Patel,M.D.,~aL,&zwzx~aawe~~ bodygnrrrdanrinthe&&!@a&z&92 J.Neumsurg362(2000) (An;BelenCarsi,M.D.,PhD.,Aripiarmmn 2 e-Medicine Journal(Dec.2001)(Aa.. 31 eg, MDR Database, M751327, Se No. datedApril 4,1996(granuloma) (Att.18); MDRDatabase, M476758, No. datedFeb. 7,1994 (paraplegia) 019); MDRDatabw, No. M213158 (%eries sllbamm~infectionsinv0lving of stemalandleg wounds”)(Att.20); MDRDatabase, M178314, No. datedDec. 1,1989(iiection) IAtt.2~; MDR Database, M178143, No. datedNov. 29,1989(infection)u; MDRDatabase, M154511, No. datedMay20, 1988(reopetion dueto post-operative draimge)w MDRDatabase, M125866, No. datedJuly 15,1986 (sternuminfection) (f&&l.); MDR Database, M117354, No. dated Jan. 13,1986(post-open&e infectionin three patients)(AL@; MDRDatabase, M101751, No. datedFeb. 15,1985(dentalstaphylococcus infection)0. Notably, the reportsin the MDR database onlyrepresentativof the extentof the pmblem. FDA itself concedes atx that the MDR database “seriousshortcomings.” has MedicalDeviceReposing(“MDR”) General Information, February l&2005 Page11 In addition, studiessuch as Robicseketal (1980)and W.K. Low and CS. Sim (2002),indicate that bone wax can embolizeto soft tissueand the venoussy~~m,causingadditional complicationsi In Robiiekaal(1980), for example, researchers the demonscrated bone that wax migratesinto soft tissuesof the lung fmm remote surgicalsites,bytagging bone wax usedin animalprocedures.That study confiid the research team’ clinicalobservationthat s abandoningthe use of bone wax as a hemostaticagentin stemotomyincisionsled to a drop in pulmonarycomplications?3Indeed,Dr. Robicseklater stated m found not only that the bone waxhasa potentialof embolizinginto the lungs but alsothat itdid not decrease blood lossiu patient cohoas where bone wax was not used Adding to this the potentialof increase infections,one in mayaskthe questionwhy should anybodyusebone wax atall? Dr. Robicsek also added: [IJf anybodyever looked at surgical “bone wax” under a microscope and could see all the insect ova, legs and fragmentsof wings, - he would think it over twice before using bone wax again!” Notably, the adverse reactionsenumerxed aboveare similar in severityto those caused by prosthetichair fibers, and someof the dons, like those caused prosthetichair fibers, even by nquited additionalconwtive operationsor pmcedwxx FDA Website,httpJ/wwwwfda.gov/cdrh/mdr/mdr-generalhtml, I%tabiy, the MDR database not include does ccmplaintsfmm pbysii and consumers.Accordingto FDA, nsea~& hasshownthat ‘ than one percentof less deviceprobEemsoccurringinhospiJsarereportedtomlA,andthemo~serioustheproblemwithadevice,the ledikeiyitwastobereported” Id 31 Annals of ThoracicSuqpy357 32FrancisRobicsek, MD., i%Etrdx&dmgc&rre WafianQanmnyZ++ (1980)(Att.;W.K.LowandCS.Sii~WaF~Bady~inrheM~640RL38(2002)(Ast.. 31 FrancisRobicsek,M.D.,lhEr?ddb&m#h Waf;mtS~Zti, 31 Annals of Tboncic Surgery357 (1980) l$a,&); seealsoFa~& Bhatti, BestBets:BestEvidence Topics,L.iteratunz Review Does TralUalUfg; . . WaxIncnzase Riskof I&d&in&, ~~/www/ the b&ets~&bm/~=OO604 co ona~reviewthatbonewaxcanembolizetothe~andthatanimalstudies~strongreasonsfor concernover the liberaluseof bone4 (Att. 14). ~4FarahBhatti, BestBets:Best EvidenceTopics,Litem Review:DoesLiberalUseof BoneWaxIncrease the . . Riskof Mediastinitis, brtpJ/www/ bestbets.og,&g-b&ets &cordpQp6p4 (with a statement from Dr. Robicsek ~AppendLrA)(Att.. 35 Id February18,2005 Page 12 ‘ bone wax usedin pnxtate brachytberapyprocedws is likely to havethe sameadverse The effects observedin the other medicalprocedures, worse. Multiple bxachytherapy or oncology ah&s have qorted that seedmigrkon to the lungsis common,and someexpertshave estimatedthat seedmigxationoccursin 1836% of all implant proceduxes?’ Given this high incidence,and the fact that the bone wax or refo&d “faux bone wax”pb necessarily rtzsides front of the liue of seeds in within eachneedle,it is reasonable conch& that the bone to waxphlgalsocommonlymigl2testQthehlngs. ?heamoumofbonew;urleft~~apatient~abrachythe~~procedureis~~~ As mentioned,during the typical prostateimplant pmcedunz,15 to 60 bx&yt.herapyneedlesanz insertedinto the prostategland,and therefore, 15 to 60 bone wax pelletsare left insidethe gland andinthesumxuAnganza. Eachbone~pluginacommerc~prepsredbitistypic~4to 5 mm long and approximately1.2 mm in diameter,and eachhasthe individualpotential to m<etothellBlgS Impoxtantly,the package insert for Ethicon bone wax, a stat&d in the bone wax industry, specificallycautionsthat “excessBone Wax shouldbe removedfrom an operativesiwn3* Obviously,that doesnot happenwhen bone wax is usedin brachytherapypxocedures. Moreover, the package insert specificallywams againstresterilkingthe product, which gene* happenswhen bone wax is usedin commercialbtachytherapykits!9 ~6 eg, MDR Database, M125866, Se, No. datedJuly 15,1986(sternum infection)&.t,&); MDR Database, No. M751327, datedApr. 4,1996) w; MDRDatabaq No. M178314, datedDec. 1,1989(infection)(Att.. 37RObertkOlder,et,~I~M~InP~T~~L~Aartrte~IIriprsbir Bttz&bq~ 165The Joumalof Urology 1590(2001)(conch&g that the incidence puhmnatyembolization of of radioahe seeds after pmstatebmchytherapy 29%) -21); Murali K. At&em, Iis @&&e Std Migdm to tk Lurp AjierPmctaieBdgtbqg 59(4)Udogy555 (2002)(fthat dioactive seedmigrationto the lungsoccurredin 36.2%of bmhythempypatients who had chestdiogmphs) (Att.; BrianJ. Davis,E)nrkrte B~S~Mignriiattothe~VeaideF~atAutopryF~AadeCwciZiPc~164’ IheJoumalof Urology 1661(2000) ~vascularmigmtionof rdioadve seeds the lungsfollowing permanent to pmstate bnxhytheqis a recognized phenomenonWe report a casein which seeds became lodgedin the right ventride”) (Aa.;SubirNag,~,gaL,Admxr#yEn~P~I~~P~lO3S~~ ctraim# index 39 Int. Journalof Radkion OncologyBiol. Phys.667(1997)(teportingthat seeds m&ted tothelungsinl8%ofthepatients~ohadprostateb~~~~;BriaaJ.Davis,etal,plmtate&aosdbprqqy SdM&nztimdoa OmxrtryAttayFd~A~ 168TheJournalof Urology 1103(2002)(iiolving a singlecasenqmt) (Att. 3Q). 38Sse, Ethicon BoneWax Package eg, Insert m. ‘ 9StEtii February 18,2005 Page13 Given that appxknately232,090 Americanmen are expected be diagnosed to with prostate cancerin 2005 aloxq40 thatappnximately4O,OOO those men will chooseto undergo and of brachythexapytreatment,” off-label use of bone wax or reformulated“faux bone wax” in the Ihe commercialbrrachythexapykits potentiallyposesa massive public heath &eat. ‘ extent of To our knowledge, there havebeenno clinicaltrials this thxeat,however,cannot yet be known. testingthe safetyof such commercialkits, many (if not all) of which havebeenmarketedwithout PM& or 510(k) &rances. Monzover,althoughsomephysicians haveusedbone wax phqgs “off-label,” any associated (to the extentthat it exists)would likely be anecdotaLFurther, data pnxtate brachytheqyprocedures have only beenpexformedregularlyfor the last 9 to 10 years, and it can take yearsfor complicationsto manifest. The use of reformulated“faux bone wax” is evenmore akming because addition to being in non-absokble, it is a completelynewpnx!uct on the market. As mentioned,it has come to our attention that certain rnanufacture~s haveintroducedto the market commercial may brachythexqykits that use reformulated“faux bone wax”plugs. We are of the opinion that manufacturers kits with bone wax pb madethe switch because bone wax plugs proved of the to be unstableduring shipping. Therefore,we believethey developedreformulated”faux bone wax” by reformulatingthe compoundsand addingfibrous substances, raisethe product’ to s melting point and to makethe pmduct lesssticky and more solid at higher temperatuxes. Because is monosolid and lessstickythan traditionalbone wax at high temperatunzs, as it such body tempenatwes, reformulated“faux bone wax”shouldbe evenman?likely than bone wax to reformulated“faux bone wax” migrateindependently from the seeds.Further, to our knowledge, hasbeen usedonly in recentlydistributedcommercialbrachythempykits,and has impactedonly appmximatelya few thousandpatientsat this point. Therefore,we believeit doesnot have a historyofuseinthehumanbody. JOSe eg, American Cancer Society Website @&m&g cancer in 2009, &m//mw.~nt/CRI cancer~36.asp?siteaa- (A,&$ that 232,090 Axmican men will be diagnosed with prostate 2 2-1X How-s D- February 18,2005 Page 14 2. ln PMAADpmal pnorto commelCia1 Dist&.ltios a. Q3!wiaY . At ninhum, given the new safetyissues raised,FDA shouldrequk manufachuers of commercia bmhythexapykits that usebone wax or reformulated“faux bone wax” needleplugs to obtain PMA approvalprior to commercialdistributior~ Suchkits are new devicesthat raise completelydifferent issues from other legallymarketeddevices.Thus, we believesuch kits should be regulatedas classIII devices, should requk PMA approval” and Indeed,we believethat comnxial brachytherapykits usebone wax or reformulated“faux that bone w-ax*needleplugs are not eligiblefor 510@ clearance alL The overwhelmingscientific at data indicatingthat comnxkal brachythe~pykits usingbone wax and reformulated“faux bone plpdxn needleplugs are dangerous, and of itself, is evidence manufacture=cannot show in that that that such kits are “substantiallyequivalent” anypnxlicatedevice,”as requinzd to under the 510(&I px0cess.4 If manufacturers were reQuired file PMAs, then theywould haveto prove that the devicein its to entirety- including all of the components,suchas needleplugs- pIesenta “reasonable assurance of safety..n45 b. . ne Wax”NeedlePlugsAte Not SubsEgivalenf’ toAqLawf@Ma&etedDevice PriortoApxil2004 To meet the “substantialequivalence” standard, new devicewith different technological a c~ristics from a p&cat.e devicemust: (1) not tie new questionsof safetlvand ‘ Sf3?21 2 u.!Lc 5 360e(Supp.2004). 43 ii Qj 36Oe(a), Se 36Oc(fj; Prernarlpet IWifiication 51O(l$: Regulato~Requkmentsfor MedicalDevices,HI% PublicationFDA, 95-4158 (Aug. 1995). u See21 USC §$36O(li), 360~0, (i) (Supp.2004);21 CFR 5 807.100(b) (2004); Premarket Not&ion RegdatoryReqtirements MedicalDe&, HHS Publication for FDA 914158 (Aug. 1995). 5100: 45Section515(d)of the FFDCA requires FDA to determine whethera devicehasa “msonable a.sswmeof safety,,” (Supp. 2004). in chiding whetherto gent or denya PMA. Se 21 U.S.C S 36Oe(d) February l&2005 Page15 dfectxveness, (2) be as safeand as effectiveasthe legallymarketeddevice.* As such,FDA d simply cannot make a legkimatefiiding that commercialbx&ythempykits usingbone wax or reformulated“faux bone wax” needlephg are “substantiallyequivalent” any lawfully to marketedpredicatedevice. As an initial matter, commercialbrachytheqykits usingbone wax or reformulated“faux bone wax” needleplugs have“different technological characteristics” any predicatedevice. No from legallymarkexed comnxxial brachyther;lpy using bone wax or reformulated“faux bone wax” kits needlephg were clearedby the FDA prior to April 2004. ‘ only commercialbrachytherapy Ihe kits that were clearedthrough the 5lO(3 processbefore April 2004,were: (1) a bm&ythempy kit using a needleph madeof bioabsorbable syx&tic suturemate&l (which hasbeenimplantedin the prostatefor many yearsin the form of “seedspacers”),‘ (2) a brachytheraEry that 7 and kit obviatesthe needfor phqs ahogetkrwith a sophisticated needledesign.* Further, brachytlxxapykits with bone wax or reformulated*faux bone wa3 phrgs,by definition haveat leastthee components- b~hytheqyneedles, seeds, phgs - and therefore,they are and technologicallydifferent from any devicethat containsonly a subsetof those components.‘ 9 Accordingly,to show “substantialequivalence,” manuf~~s would haveto demonsttatethat . the kits: (1) do not tie any new questionsof safetyand effectweneq, d (2) are as safeand ’ effective as a predicatedevice. We believeman&rs cannotdo so because bone ivax and reformulated“faux bone wax* pb tie questionsof safetyand efficacythat are exceedingly . 46Se id 5 36Oc(i); C.F.R.S 807.100(b) 21 (2004); Pmnarket Not.Zkuion 510(@Reg&to~Requirementsfor MedicalDevices,IdEB Publication FDA, 95-4158 (Aug. 1995)(emphasis added). 47Sac, World W& MedicalTechnologies, eg, 510&)No. K022389, May6,2003 (Art.. 48Sap, ImagynMedicalTechnologies, eg, 510&)No. KO10166, 3,2OOl(&t. 33). Dec. 49To the extentthat there arecanmenial brachytherapyneedles plugged with bonewax or nzformulaed“faux bone v&‘ onthemarket,theyshouldbe&atedasclassIIIdevices. ‘ The-yshouldnotbegovernedby21CF.R.~ 892.5650, which qplates “manualmdionuclide applicator systems” unphqgedbrachythenpyneedles their (eg, and componentpaas and accessories) class I, 510(k)exunp devices.In 1982, as FDA class&d mamul radionuclide appliaxs (includingthe genericdevicewith components access&s), under21 CF.R. $8925650,as classI and devicesbecause could not identify anyrisksto health Se 47 Fed.Reg.4406,4438 it (Jan. 29,1982). However,at that the brachytherapyhad yet beenperformed,Indeed,the fust brachytheqypaeduxes werepexfonned not in 1985. See John E. $&ester, UD., M&BOncologyIssues(May/June2002)(&Q&)34). Thus,we do not believe FDA could havecontemplated brachytherapy that needles plusged with bonewax could everfall under that section. Moreover,brachytherapy needles plugged with bonewax or reformulated “faux bonewax”tie the samesafetyissues brachytheqykits because inject non-absorbabk as they plugsinto the body. February 18,200s Page 16 different from those tied bythe predicatebxxchytherapy which either do not use pb kits, all or use phgs madeof bioabsorbable syntheticsutunzmate&l. at As summarkedabove,overwhelmingscientificdataindicates “bone wax”pb present that signifii safetyrisks because do not absort,into the w they As such they could trigger the body%defensesystem,actingas a cat&t for many complications, in&ding chronic inflammation (ganulomatis infection),markedfox.Ggn bodyxtxction, sa~~omas/angiosarcomas (ie, blood vesselcancer),epistaxis, a&+ reactions,sign& sinusthrombosis,foreign body venousembolization,and it could evencontributeto quadriplegia, amongother things.%In ~~thep~ofbone~couldmigratetothe~wheretheycouldcausefurcher complications.51 Refoxmulated “faux bone wax” maybe evenworse. We believereformulated “faux bone wax- posesthe samesafetyrisk as bone wax because cannot abso& into the it body, and it maypose unknown additionalrisks,giventhat it doesnot havea well-established historyofuseinthebocfyforanypurpose(ifam/historyat~.52 The bmchytheqykits on the marketthat do not usebone wax or refomwlated “faux bone wax” do not tie thesesafetyissues because either do not usephgs at all or the phgs are made of they syntheticsunne mated that absohs into the body? Notably, biiabso&able synkic sutu~ material,unh bone wax or reformulated“faux bone wax,* is welLestablished safefor use in as soft tissue. For example,the FDA clearedsyntheticbioabsorbable sutunzs, use in soft tissueat leasteight for clearedthe use of syntheticsuturefor use as seeding yearsago.%In addition, FDA specifically spacermaterialin brachytherapy over five yearsago,‘and has sincecleareda brachytheqy kits ” M Se sz@qdiscussion SectionC(l)(b) herein. at 51Seszpq discussion Sectionc(l)(b) herein. at 52 szqm,discussion Sectionc(l)(b) herein. Se at 53 Labeling Se Information for Monoc+ @dicatingthat bioabsorbabIe qmhetic suture,whenusedasa tradkional suture,cmld leadto signifiitly h seven5 advenereactions, suchas%&ction~ aud”minimal acuteinfkmamry tissuereaction”)0. No. Dec. l&l996 @tx.36);stmk&lonoc~ 9 Seqeg, Ethicon, Inc., 510(@ K964072, Information Sheet(Att. 37). (Poliglecaprone 25) 55 .%Indigo MedicalCo., 510@ No. K992262, Oct. 4,1999 (&LX!); stzut!w World ‘ VP& MedicalTechnologies, 510&I No. K991344, Nov. 5,1999 (Atc.391. February18,2005 Page17 kit that usessyntheticsutw to phg the brachythe~needles.56 In stakcontrast, to the best of our knowledge,bone wax and reformulated“faux bone wax,”as stancklone products,havebeen clearedonly to stop bone bleedinglocall$”- they haveneverbeenclearedfor use in soft tissue. Theneare a number of companies advereising comxxz~~ial brachytheqykits that promote the useof bone wax or reformulated“faux bone wax”~hgs.~ Gxnmercial brachytheqykits that use bone wax or refoxmulated“faux bone wax”needlephgs overdyraisequestionsof safetythat are new and different fmmthose raisedbythe brachytheraprkitsthat were on the market prior kit to April ZOO+ and pose a potential public healthth~at. Acco&&, any suchbmchytherapy should nquk PMA appmval,rather than a 510(k)clearance, prior to commercialdis&utk c. . May Have Cleazed K&s . . Two New Brachythem-py . via t& Potex&&y Use Bow 510(k)Pmcessm &pl and)& 2004.dr;lty or Reformulated “Faux BoneWax”NeedlePlugs Publiclyavailableinfomution suggests two recentlycleared that bmhytheqykits may potentiallyuse bone wax or reformulated“faux bone wax” needlephgs. As shown above,we believesuch kits would requk a PMA, rather than a 510(k),because they&e questionsof safetythat are different from those raisedby brachytheqy kits with 5lO(@clearance pxior to April 2004. Accodngly, to the extentthat the two kits containbone wax or reformulated“faux bone wax” needleplugs,we believethat theywere likely clearedin error. Basedon the infornration available, FDA may haveoverlookedthe fact that thesekits potentially use bone wax or refounulated“faux bone wax”plugs and/or wasunam of the safety implications. Indeed,the information pnwided in the 5lO(lj summaries the devicessuggest for that needlephqs are neededfor the kits, but fail to mention the type of needlephgs usedand fail to cite predicatedevicesthat use bone wax or reformulated“faux bone wax”needleplugs. On July 16,2004,FDA cleareda brachytherapykitsubmittedby InternationalBrachytheqy, S.A. (“I&“), 510(k)No. KO41702.The onlypubliclyavailableinformation about the IBt kit is the 510(k) summary,which makesno mention of the type of plug usedwith the brachytherapy needles. The 510(k)summarymerelystylesthe new device,E&Pal? , as “a packaging change” 56 World W& MedicalTechnologies, Se 510(@ No. 022389, May6,2003 (An.. 57Se eg, United States Sugical Chporation, 510(@ No. K971680, Oct. 24,1997 (claiming ‘ substantial equivahcem with Johnson &Johnson’ Ethicd” s (preamendment) ad Luke&“ Bone Wz (K791405)) m; ’ Q? Medical, Inc., 510(k) No. K024372, June 19,2003 (A&& saSee, Miscellaneous eg, PromotionalMaterialfor Kits UsingBoneWax or ‘ Faux BoneW’ Plugs(A@. ax” February 18,200s Page18 to previousproducts marketedbythat company- ie, Intetsou~e-103,Intersourc~125, and Intemd@ . Indeed, a readingof the 510(k)summaxy EZ-Pak” and the 510@ summary for for Intexstrand@ suggests EZ-Pakw is Interstrand@(k, a strand contain& radioactive that seeds(Intersource*) and spacers) “repackaged” brachytheqyneedles. into However, &is “tipac~ is not as incidentalasthe 510(k)s-for EZ-l?akm suggests. It is extraox&arilymaterial because prepac~ the necessitates use of a phrgto securethe the contentsof the needleduring shippingand subsequent handlingbythe swgicalteam members,as well as additionalswilization pnxedunx - both of which potentiallyhaveattendantsafetyrisks, paaiddy if the phg usedis madeof bone wax or reformulated“faux bone wax.” (As mentioned,the package insert for Ethicon bone wax specifically cautionsagainstrestexilkingthe plAlct):9 Yet, the SlO(l$ summaryfails to referenceanypndicate devices@ other than Intersounx-103, Intersouce- 125, and Interswd@ , none of which utilizesbone wax or reform&ted “faux bone waxn plugs!’ In fact, the 510(& for those devicesspecifii statethat the only mat&ah that come into contactwith the bodyaxetitanium and, in the caseof Intexstrand*, sutue materiaLa There is no mention of bone wax. In this instance,we believethat the IBt brxhytherapykit, EZ-Pak” , doesuse bone wax or reformulated“faux bone wax” needleplugs- despitethe omissionin the 51O(l$summarybecause descriptionof Interstrand@in IBt’ own advertisingmaterialcontemplates use of the s the the strand with a bone wax phg as follows: “Intexstrand@consistsof 10 Intexsouxe@seeds threadedinto a monofilamentabsoxbable sutute. The seeds spaced1 cm apart measured am centerto center. Intend* easilypenetrates standardbone wax phg, the 59 Ethicon Bone Wax Package Se Insea (Att.31). 60SeIBt EZ-PakBt+&erapyKit, 510(@ KO41702, 16,2004@tt. 40). No. July 61SEeIBtInterstrand,5100 No. KOlll55, July 12,200l (specifiistating that the onlymatetiahcontacting the bo(y aretitanium andsuturexnaterial) (&&); IBt Intersouu-125,510(k)No. K984235, June9,1999 (se stamg that the only materialcontacting bodyis tziabm) 0; the IBt Inteaounce- @seed), 5 IO@ No. 103 K973328,Dec. lo,1998 (same) (Att.43). 62SeIBt Inted, 5lO(l$ No. K011155, 12,200l (specifiiystating that the onlymateriascontact& the July body aretitanium andsutm material)(Art.; IBt Intersource-125,510(k) K984235, No. June9,1999 (specifidy statingthttheonlymaterialcontactingthebod y is titanium)-42); IBt Intetsource- (herseed), 510(k)No. 103 K973328,Dec. lo,1998 (same)(/ht. 43). February18,2005 Page19 ninbizes seedmigration,and reduces prep time . . . . Benefh . . . Easily Penetrates Bone W~X.*~ The 5lO(l9 for the bmchytherapykitsubmittedby BEBIG Isotopen-undMedizintechnikGmbH (“BEBIG”), which was clearedby FDA on April 8,2004, is silent with regardto whether the kit usesneedlep~andwithregardtothetypeofneedlepluguse~-&spitethefactthataneedle phrg would likely be necessarytosecurethe contentsof the needleduring shippingand subsequent handlingbythe surgicalteam nwnbers. Indeed,the 51O(l4summaryspecific* cornpamsthe Upackagin$’ the BEBIG bmchytherapykitto the stmnd that is cited as the of predicatedevice,but it only mentionsthe “implantation needle,” the needleplug. Moreover, not none of the predicatedevicescited usebone wax or reformulated“faux bone”wax needlepltqg. 3. . . . FDA ShouldRescmdAnv CurrentuSubs@@al Eaumlenceb Order for . Bmchmv I& that Use BoneWax orRefonmlated cc Faux Bone Wax” Absenceof Slotkl Cieamce Regadlessof whetherFDA decides ban brachytherapykits usebone wax or reformulated to that “faux bone wax” needleplugs,or to rwquimPMAs, FDA shouldrescindany existing“s&tan&l equivalence” ordersfor such kits (specifically, ordersfor the BEBIG and IBt kits, m the the extent that they usebone wax or reformulated“faux bone wax* needleplugs). As a matter of come, paxkhdy given the associated safetyissues, FDA should alsoremovefrom the ma&t any such kits without 510(k) clearance PMA approval or FDA hasthe authority to rescind“substantialequivalence” orders (1;c,51O(l$clearances) cases in risk that involve: (1) a seriousadverse to healthand human safety,(2) data integrity or fraud, gg (3) other compellingcircumstancesP5 the extent that the IBt or BEBIG brachytherapykits To use bone wax or reformulated“faux bone waxmneedleplugs,we believethat all of theseelements could be implicated,althoughjust one of thesegroundswould be sufficient for rescission. First, and most importantly, as detailedin SectionC(l)(b) herein,we believeoverwhelming scientificdata indicatesthat “bone wax”plugspresentseriousadverserisksto health and human safety, Because bone wax plugsdo not absorbinto the body, they could trigger the body’ the s defensesystem,actingas a catalystfor many complications, includingchronic infkmmation 63 Intemrand Advertising&&p&J IBt 6) !k BEBIG Brachytherapy 510(k)No. KO40339, t&2004(Att.. Kit, Apr. 65Se 66 Fed. Reg.3523,3524 16,200l). (Jan February 18,2005 Page20 (gnudornatis infection), markedforeign bodynzactio~ sarcomas angiosarcomas), (eg, epistaxis, allergicreactions,sigmoidsinusthmmbosis,foreign bodyvenous embolization,and it could even coxltirhamquadtiplegia66 Inaddilio~thebonewlaxphlgscould~mthehlIlgswhere they could causefurther complications.67 As mentioned,we believereformulated“faux bone wax”presentsevengmxer adverse risks to health and human safetythan bone wax. Reformulated“faux bone wax” can causethe same complicationsas txaditbnal bone wax because cannot absott,into the body. Moreover, given it that refomulated “faux bone wax,=to our knowledge, doesnot havea histmyof use in the body for any purpose,it could causeadditionalinjuriesP” Second,addtessing third element., the other compellingc-es are present. As detailedin Sectionc(l)(b) herein,assuming the BEBIG and IBt bmchytherapykitsusebone wax or that reformulated“faux bone wax” needleplugs,the kits presentdmmaticallydiffenm issuesof safety than the pnxlicate brachythempykits,which either obviatethe needfor phgs thmugh needle designor useplugs madeof bioabsorbable syntheticsutw mate&l. Acconlingly,they are not “substantiallyequivalent~ the pmlicate brachythexqykits - and the Wmmtial equivalence” to orders,in our view, should not havebeenissuedin the first place. Finally, addmssing secondelement,althoughwe havenot seenthe actualSlO&) submissions the and therefore am not in a position to kaow for certain,there may be reasonfor one to question the integity of the data submittedto FDA in the SlO(l$ssubmittedfor the brachythempy by kits IBt and BEBIG. Assumingthat both BEBIG and IBt are in fact using needleplugs,FDA should revisit the datathat the companies submittedin their 510&) applications determinewhether to the type of plug was disclosed Accoxlingly, assuming IBt and BEBIG axeusingoff-label bone wax or reformulated“faux that bone wax” phgs in their brachytherapykits,FDAhas more than sufficient groundsto rescind the “substantialequivalence” orders,and it should do so immediately Given the safetyissues associated bone wax and reformulated“faux bone wax” and the problemswith showing with “substantialequivalence,” FDA should alsoact immediatelyto rescindany other “subst.an&l equivalence” ordersthat have beenissuedfor comme&l brachytherapykitsusing bone wax or reformulated“faux bone wax” needlephgs, to the extent that there are any. 66Se sripnr, discussion SectionC(l)(b) hen&. at 67See sqm, discussion !kction C(l)(b) herein. at 68Sesqiq discussion SectionC(l)(b) herein. at Page 21 D. Nothingrecp~ted impact on the envitmmmt, and thus, &its petition &ould be catcgndenlxp excluded horn anp applicable rc&ements in 21 C.F.R pt 25, subpt. C (2003) and 21 C.F‘ 5 25.40 (2003). -R. _ 421 3n ti petition dll have a E. - . . The uncextih thaq to the beat knov&xlgc and b&f of tIae undr~4 this petition i.twh+ all itxhmaiio~ and views on wbi& the p&ion z&s, and rhilt it inch&a rqmemi+e data nad infcmrmtioti lcnowr~ to &e pe&iorm w&h pt;c unkvrxable to the @ ion- * * * * . * For the reasons listed hw FDA ahAd immedintiy take action to ?XI the onle of co. lamchepy kits that USCboric wax or zefoma&zed ‘ %aux bone was? ne&e phrgs. In the ~tive,FDArhouldkam~~~~~~~~ofsuchdcvicGstoob~PMA + approval for their kits, rather than 510(k) cleanance. Ia addition, FDA should mcind pay that FDA exe&se its nutbozity over &sting SsO(lc) czleamnccm~ such products. It is iaaprah fix those &victca to protect bchythapy ptticnts fkom’ the potential deyirmca nasocktedwith bone wax and reformu&tted “fiwx bone wm? needle plug. . February 18,200s Page22 Tiithykulamwski Director, Office of Compliance Center for Devicesand Radiological H&&h Nancyc. Bmgdon Dinxtor, Division of Reprodwtive, Abdominal,and Radiological Devices Office of Device Evahation Center for Devicesand Radiological Hkakh Mr. Gilin Fiima Bmnch chief Office of Compliance Centerfor Devicesand Radiological Health Robert k Phillips,Ph.D. Fief RadiologyDevices Bmch Division of Repmductive,Abdominal and Radiological Devices Office of Evahxuion Centerfor Devicesand Radiological I-k&h MaxjorieShuhnan ConsumerSafetyOfficer Pmmrket Notification Section Center for Devicesand Radiological Health