ectiveness Rummm GENERAL INFORMATION Device Generic Device Trade Applicant s and Address Arrow International Highway 1600 Providence Massachusetts Walpole Name PMA Number P890055 Date of Panel Recommendations March 1991 5 INDICATZONS FOR USE The approved contraindications labeling Valve Pump with Bolus Safety Implantable of 2 delivery intra arterial regional and normal saline saline heparinized the indications of the drug in the for FUDR stipulates for use and warnings are water or saline Bacteriostatic of FUDR concentration may be used saline Heparinized of FUDR an interruption during catheter to maintain therapy patency to be used to achieve is pump the desired DEVICE DESCRIPTION Flow The Model 3000 Constant Pump with Bolus Implantable called hereafter Valve Safety Pump non is a disk shaped infusion pump programmable for designed to be implanted a of delivering the purpose flow of medication continuous It body site to a specific has a body 7 8 cm in diameter Located on and 2 4 cm high its top side is a domed center 1 0 cm high septa port IC 02081 MAR I I Flow The Model 3000 Constant continuous for the indicated FUDR deoxy 5 fluorouridine water bacteriostatic ZIZ Pump Flow Implantable Model 3000 Constant Valve with Bolus Safety Name Date of Notice to of Approval the Applicant IZ Pump Infusion Non Programmable Implanted Name Sllt111 LOOp Catheter SEptQR Septal Eody Pigure Height fht Hei l External Schematic of Model 3000 Pump Once 1 of 3 4 cm see Figure an overall pump height providing septa center the through is accessed the Pump implanted percutaneously injection a bolus and the refilling of both providing pump for purposes 0 6mm O D 2 3mm exits catheter ID outlet rubber A silicone loops are spaced around the body Four suture from its edge tangential of the Pump for securement The domed septa port houses septa rubber two silicone on center vertically aligned between is inserted A spacer an creating septa these This gap is interseptal gap end of the bolus the proximal from the leads which pathway to interseptal gap directly bypassing catheter the outlet the flow restricting of the pump see mechanism 2 Figure opt a ath Soleil tath ketill 4 41 1010 VL1TI trapallLDt Oatlot Catheter liame Tilt X LagalDC4X Dkag RDII IoIorT01c Illfll4ie4 AeIaablf NOO414 ItOp a The Pump incorporates the Bolus Safety valve the bolus within Valve Schematic 2 Cross sectional Figure the to prevent pathway of fluid administration is positioned the pathway in the event the tip of a needle through was added to an earlier This feature the interseptal within gap events bolus of inadvertent to reports of the Pump in response version and cup lever spring spool of a valve consists assembly The valve the When the Pump is accessed is closed of the valve The normal state in the cup lever and depress both septa tip must pass through needle to open for the valve order to which have been welded upper of a center The Pump body consists plate respectively the upper cover and can called shells and lower titanium into two divided can is the and by the center The space enclosed plate chamber of the bellows bellows The interior by a collapsible chambers is 30 The volume of the drug reservoir is known as the drug reservoir surface of the bellows The second chamber formed by the exterior ml The Pump is powered by chamber and the can is known as the propellant a two phase propellant exerts the propellant When the Pump is implanted 37 C of a temperature at of the bellows exterior fluid contained forcing the the bellows collapse a capillary flow restrictor a filter through plate Figure 2 to the body the catheter see on the pressure acts This pressure in the drug reservoir and then through tube with an internal of a capillary consists The flow restrictor to obtain is varied The length of the tube of 0 05mm diameter is also flow rate ml day Note however rates from 0 5 to 2 0 2 flow to and drug altitude on temperature dependent reservoir drug between the difference pressure catheter on distal which depends placement viscosity and the as well as the outlet pressure is or bolus injection of the pump for a refill access Percutaneous necessary is needle specific a however manner the same in accomplished the Pump to When accessing successfully each procedure to perform is needle non coring 22 standard a reservoir drug the gauge refill the of distal most at the opening has an portion needle This used are both septa is correctly When the needle shaft positioned needle in the seated until advanced fully is tip needle the and penetrated is also of the needle the opening Thus chamber below the lower septum chamber lower This septum lower the below the chamber in contained of Injection via a hole with the drug reservoir communicates directly correctly Although drug reservoir the fills chamber into this fluid the does depress a refill into the Pump to perform the needle inserting affected flow the valve safety bolus passages and opens the cup lever by the valve are not in the fluid path for normal pump refill a refill during no purpose serves the valve in effect Therefore the refill the event In when it is correctly performed procedure the within stops and both septa through is not inserted needle infusion a direct closed remains the valve interseptal preventing gap the bolus pathway through bolus a special a bolus injection the Pump to perform When accessing an and opening sealed is needle The tip of this is required needle is needle When this shaft down the needle has been created partially needle the stop needle to the and advanced both septa inserted through tip the needle Additionally within the interseptal aligns opening gap for valve allowing bolus the safety opening the cup lever depresses manner In this catheter with the outlet communication direct to directly space is delivered into the interseptal of fluid injection as a bolus injection the patient one 1 needle with one 1 22 gauge non coring Each Pump is packaged a Record for Use a Pump Implant Instructions Bolus Needle Special and a an O R Record Booklet Education a Patient ID Card Patient Record Physician This kit to aid in performing A refill kit is available pump refills set to a 12 tubing needle attached incudes one 1 22 gauge non coring an extra 22 gauge non coring with one way stopcock a 35 ml syringe three cap syringe drape fenestrated a plastic a non absorbent needle two 2 gauze two 2 alcohol swabsticks 3 povidone iodine prep pads abc Instructions sticker dressing a Patient chart an adhesive pads For Use 3 lP ZV COHTRAZNDICATZONS The Pump is conditions for contraindicated Known or peritonitis suspected use infection with bacteremia septicemia 2 reaction of allergic Known experiences devices implanted to intolerance 3 Emotional 4 Those whose size of the or psychiatric body size pump the in patients or other following or of signs problems is insufficient to accommodate the drug Pump in the approved specified the contraindications In addition in the drug the using when product must be observed labeling V physical WARNINGS medical only by qualified and refilled be implanted The Pump should of servicing and use in the surgical knowledgeable personnel to implant specifically and trained and catheters devices implantable trained not properly Use of the Pump by personnel the Pump or refill consequences to serious lead may servicing and or implantation in its In the of drug to the patient under or over delivery either involving labeling drug approved to the of drug refer event of an over delivery action for appropriate storage handling filling the proper of the Pump requires Utilization of amount This of drug volume dosage of a significant and dispensing or suddenly if delivered harmful to the patient drug may be extremely inappropriately the using must be performed and pump refill Bolus access procedures a Special to refill the Pump using Never attempt needle access correct to the injection a bolus in giving This use will result Bolus Needle overdose fatal drug a and may cause patient VI PRECAUTIONS REGARDING THE USE OP THE PUMP Aspiration fluid from the Pump Never aspirate in occlusion and result drawn into the catheter will cause blood to be to access needles Bolus or Arrow 22G Non coring Only use Arrow Special of the pump septum to the integrity It is critical the pump septum the septum be used to penetrate needles no other that It is order instructions the Pump refill follow important to precisely If the Pump refill complete to successfully procedure 4 lW the in needle and verified is not properly positioned drug is a possibility there Procedures a bolus Before performing indications precautions as detailed extravasation in the Pump Refill will occur review all on the drug of any drug injection and contraindications warnings labeling a bolus system to accomplish injector Do not use a mechanical pressure a when administering should not exceed 40 psi Pressures procedure larger ml 10 only or use For injections or infusion injection bolus than 5 ml min at a rate greater or infuse and do not inject syringes a bolus while performing with saline When the system is flushed equal to the drug a bolus dose of will receive the patient procedure the Pump plus of bolus pathway in the internal volume of drug contained in the internal The volume of drug the volume of drug in the catheter in the The volume of the drug contained of the Pump is 0 3 ml pathway catheter the the length in cm of by multiplying is calculated catheter by 0 003 ml cm INFORMATION FOR THE PATXENT that may cause activity from physical refrain should The patient or the pump itself site to the area near the pump implant his notify should The patient noticed are symptoms unusual The patient from running tip must dry should The patient to alert emergency return which or her physician refill on established might lead to thrombus carry health immediately if times to prevent at the formation caro in case ID the Patient of the presence care workers before contact their should The patient physician flow rate affect Changes in ambient pump pressure of drug to the patient under or over delivery injury any the pump catheter of a medical of the pump by air traveling which may lead to or take long not use a heating should The patient pad over the pump site ambient decreased and Elevated temperature or saunas hot baths the flow rate of the pump which may lead to over increase will pressure delivery of drug to the patient if they have an increased inform their should The patient physician the flow rate will increase Elevated body temperature temperature to the patient of drug the pump which may lead to over delivery The patient altitude pump which if they move to a different inform their should physician of increase the flow rate will ambient pressure Decreased of drug to the patient may lead over delivery The patient should the drug labeling be informed of the 5 appropriate precautions listed body of the in Booklet Education a patient be provided should should be thoroughly in the booklet contained implantation to prior The patient information the patient Alternatives described VZIZ PRACTICES ALTERNATIVE by to prevent a bolus infusion withdrawn is If the needle septum of the Pump drug throughout remain still should The patient Needle Bolus Special the any movement of upper the above lumen the amount exposing occur may extravasation VII and the understood an AND PROCEDURES to use of the are as follows solution of the drug injection syringe and a needle 1 Intermittent system via 2 administration Continuous parenteral utilizing set and catheter an I V infusion pump drug the pump to deliver solutions into of the drug either gravity the previously vascular through solution or an external MARKETING HISTORY An States in the United approval marketing The Pump has never received Valve Safety Bolus the contain not of the Pump which did version earlier and Belgium the Netherlands France Spain in Germany was marketed version This 1991 May through 1990 January the period Denmark during of incidents reported after from these markets of the Pump was withdrawn through to of drug products administration patients bolus inadvertent the pump bolus pathway One in Germany and Canada the Pump has been marketed Since March 1993 A has been reported failure a device post involving event adverse the capillary indicated device for this report analysis failure explant a weld procedure in the Pump was damaged during tube contained situation this action has be taken to correct Appropriate IX POTENTIAL ADVERSE EFFECTS OF THE DEVICE ON HEALTH The potential adverse effect of device the is as follows a corrective would require failure A device Device failure in would result failure the addition In surgical procedure flow or an amount of the of the medication a stoppage either tissue into the subcutaneous escaping medication Other potential 1 Catheter complications thrombosis are as occlusion 6 follows This can occur if the pump the catheter and the blood enters flow stops becomes empty the surgical procedure could also occur during occlusion Catheter This catheter the ligating and tight too sutures the by tying to the sutures to relax a surgical procedure might necessitate flow regain 2 3 4 with the implantation This can be associated Infection and may involve refill the or procedure the device procedure might necessitate This or catheter pump pocket pump reservoir infection the clear to device of the the explantation the of rigorous because migrates If the catheter migration Catheter a different in medication the receive would the patient exercise to surgical a necessitate procedure This might area of the body therapy for proper the catheter reposition is sutured device If the skin over the implanted Skin necrosis might This could occur then skin necrosis too tightly the pump in another to reposition a surgical necessitate procedure of the body location This could occur if drug is accidentally the refill during procedure pump pocket of therapy discontinuation temporary 5 Drug extravasation into the spilled might necessit ate 6 to the too cIose is positioned If the catheter sheai Catheter of the shearing implantation rib during and first clavicle a surgical This might necessitate procedure may occur catheter the catheter to replace 7 of from the injection This results Bolus path occlusion and bolus the through solutions pathway particulate and the pump materials between a bolus solution incompatibilities but might the bolus pathway by flushing This may be resolved and or catheter the replace to a surgical require pump procedure 8 suture breaks This could occur if a securement Pump dislodgement This activity in rigorous or the patient physical participates the or reposition attach to a necessitate surgical might procedure pump 9 with the implantation This can be associated leakage Catheter This results breakage or catheter refill procedure procedure than the the body other area of of drug to an in the delivery or replace to a surgical This requires intended site procedure the catheter repair 10 This can be associated error Bolus injection a refill needle during selection of the access in may result needle of the incorrect Selection of drug to the patient volume dosage significant if to the patient drug may be extremely harmful or inappropriately 7 This with an incorrect or bolus procedure of a the injection This amount of delivered suddenly X SUMMARY OP A In Vitro STUDIES Studies was conducted Testing reactivity biological 1 Bellows the mechanical to characterize of the Pump of the components performance Tests would a the bellows which demonstrated were conducted Tests a liquid b maintain of the propellant the pressure transmit c hold and device of the life the over barrier impermeable envelope design allowable the in remain and drug 2 Catheter and effectively and vapor 30 ml of Tests to the Pump of the catheter The connection Integrity Joint Catheter Catheter load an axial withstand joints to ability its for was tested to load axial an increasina to subjected were Pumps assembled on fully to from 3 1 ranging loads at occurxed units test of Failure failure 3 7 lbs material of the catheter The integrity Integrity Material Catheter catheter of the Segments test load a tensile using characterized load to failure tensile to an increasing were subjected material lbs to 5 5 0 from ranging at loads failed catheters Tested was neir to ability to assess were tested Catheters Burst Teets Catheter to were subjected Catheters operating internal withstand pressures ruptured catheters Tested rupture until internal increasing pressure at 130 to 135 psi 3 Septum Tests Testing Life Test Septum Puncture of the septum material life puncture in installed upper and lower septa both with 22 repeatedly punctured of 50 to at a ratio needles bolus of air by the formation evidenced water in bacteriostatic submerged septa 40 All to psi pressurized 1500 pictures Septum Proof Pressure of the septum ability operating pressures to 200 psi subjected and in place remained were observed was Testing Test and septum material Septa were installed internal pressure did not blow out of 8 7 to de rmine the was conducted of cczsisting Sub assemblies were hczsing assembly the septa and special need as gauge non coring was Sep a leakage 1 respectively was when the sub sembly bubbles was and the interseptal g sign life of beyond the performed the to de ermine conducted internal to w hstand assembly and into pump su assemblies to ted the septa In all units No leaks the sub assem y of the integrity to assess was connected Testing Loop Pull Test Suture loads 1bs 10 to subjected were loops Suture loop and joint the suture was seen under 30X of failure No evidence in each of five directions magnification 4 Bolus Safety Valve Tests Test Valve Function The Bolus Safety Teet Valve Punction Bolus Safety 40 of a withstand pressure of the valve system to the ability evaluated bolus the through flow fluid and permit state psi in the normal closed was performed This test injection bolus simulated a during pathway cycling thermal states eg or wear inducing to stress subsequent on impact the states to verify in order etc sterilization shock function valve Sterilization Product on steam sterilization to Pumps were subjected all sterilization After Valve to a Bolus Safety of a pressure withstood the through flow fluid of the effect to assess was conducted Testing Assembled of the valve assembly the performance cycles steam sterilization 2 or 6 production each unit was subjected were completed cycles in all units The valves Test Function and permitted state 40 psi in the normal closed bolus injection a simulated bolus pathway during of shock loads the effect to assess was conducted Testing Shock Test were dropped Pumps Assembled assembly valve the of on the performance with 1 inch covered floor a concrete onto feet of 3 height from a xyz coordinate along an 6 impacts to subjected was Pump Each plywood of all application the After center at the system established pump Function Valve Safety Bolus a to was subjected each shock loads pump of 40 psi in the normal closed a pressure wiihstood All units Test a the bolus pathway during through fluid flow and permitted state bolus injection simulated of thermal the effects to assess was conducted Testing Cycling Thermal with Pumps Assembled valve assembly of the on the performance cycling 4 to were subjected water bacteriostatic with filled flow pathways of 24 hours at 17 C and 24 hours at each consisting cycles thermal to a Bolus Safety cycling each pump was subjected thermal After 21 C 40 psi in the of a withstood All units Test Valve Function pressure bolus through the flow fluid and permitted state pathway normal closed bolus injection during a simulated the to assess Testing was conducted Valve Proof Preesure Bolus Safety operating internal of the valve system to withstand pressures ability was inserted into the interseptal needle A non coring gap of assembled cycles to 25 pressurization The interseptal units gap was subjected to 200 psi back to atmospheric atmospheric pressure covering pressure for fluid catheter of each unit was monitored the outlet During cycling flow was No fluid the bolus pathway flow through flow indicating each pump was cycles After all pressure from any pump observed a withstood All units Test Valve Function to a Bolus Safety subjected fluid flow and permitted state of 40 psi in the normal closed pressure bolus injection a simulated the bolus pathway during through 9 the to assess was conducted Testing Test Valve Cycling Bolus Safety Pump the of life design over the of the valve assembly performance needle with a 22 gauge non coring were repeatedly punctured Units of air cessation and by the appearance was verified Valve operation interseptal the when gap was catheter at the tip of the outlet bubbles of observance the or every 250 punctures After to 2 psi pressurized was Test Function Valve a Bolus Safety any anomalous performance of life design beyond their units All unit each performed on performed 1500 septa punctures which of 2 0 rings The valve gland consists Valve Gland Cycle Test between as a barrier of the valve spool acting shaft seal the moveable to was conducted Testing reservoir drug the and the bolus pathway of the life of the valve gland over the design the performance assess the duplicating of the valve gland were cycled Sub assemblies Pump bolus or refill a during procedure components valve the of action 10 psi air with by were tests leak pressurization Periodic performed sub assemblies All performed formation by bubble was evidenced Failure cycles 1500 of life beyond the design 5 Tests Filter to determine sub assemblies on filter were performed tests Bubble point the filter indicated results Test material the pore size of the filter diameter in 0 2 than had no pores greater pm material 6 Joint Capillary Tests to of the capillary the ability joint to assess was conducted Testing articles test No cycles autoclave and repeated high pressure withstand Joints to 160 psi when pressurized of failure showed an incidence loads of 0 8 to 1 0 lbs under axial failed 7 Shelf Life Tests to assess the was conducted Testing over time sterility device maintain to maintain material of the package 8 ability Test sterility to material of the package ability the data demonstrated at a two year test point Flow Testing fluid of the Pump to deliver the ability to verify was conducted Testing at were flow tested units Assembled over time flow rate at a constant water and a 0 01 C using both bacteriostatic of 37 C a temperature Flow variations and heparin 2000 U ml mixture of FUDR 20 mg ml No rate spring to the bellows were attributed from mean flow rates contents reservoir its expelled rapidly pump 9 Testing Shock and Vibration was conducted Testa in accordance 10 with the National Safe and Transit to assess 1991 April Test Procedure NSTA Preshipment Association conditions shipping simulated under vibration and of shock the effects were units unpackaged and Packaged Pump of the on the performance tested and vibration and post shock were performed Flow tests pre water was bacteriostatic using cycle flow A calibration conditioning for rate in flow No differences in performance changes used to measure in a decrease exhibited units Packaged were noted units unpackaged flow rate of 0 02 ml day Leak testing conditioning were detected 10 and vibration and post shock was performed pre leaks of for the presence to test propellant No leaks Studies Biocompatibility of the pump the biocompatibility to assess was conducted Testing in were tested materials contacting All blood and tissue materials and Pharmacopeia of the U S sections with relevant accordance Devices September for Medical Guidance Biocompatibility Tripartite for is appropriate of the pump materials The biocompatibility 1986 use the intended 11 Test8 Compatibility the pump fluid between the compatibility to assess was conducted Testing incubation After drug indicated and the materials products path from 43 50 days at 37 Ci0 1 C ranging pumps were disassembled periods No and corrosion of degradation for signs and examined microscopically were observed of degradation nor signs build up foreign 12 Stability Tests drug of the indicated the stability to assess were conducted Tests alone of heparin stability Pump The in the contained when products with FUDR in combination 1000 heparin 10000 U ml and and U ml 1000 in assembled when contained was studied 1 0 mg ml FUDR heparin U ml Eluant at 37 C ranging for periods from 42 to 50 days incubated units incubation the over were collected reservoir samples catheter and drug HPLC method using a suitable was determined FUDR concentration period Clotting Time Thrombin using the was determined Heparin concentration assay The test is stable B Animal that heparin data indicate in the Pump at 37 C over alone and in combination a 6 7 week period with FUDR S tudies the in vivo performance were conducted studies to evaluate Two animal of studies in to initiation of FUDR prior the Pump for the infusion 21 1987 Between July 16 1987 and October five human subjects 5 11 of in four 4 mixed breed were implanted version Pumps of the earlier A two week artery hepatic in the common were placed Catheters hounds heparinized of infusion week with a two of FUDR was alternated infusion when the development was discontinued FUDR infusion saline 1000 U ml of serum glutamic levels in by increases was evidenced of hepatoxicity transaminase SGPT and alkaline phosphatase pyruvic implant Average days of 485 implant consisted Total pump experience 0 77 0 17 were 0 81 0 16 Average flow rates was 92 days duration stoppage failure ie One device ml day and 0 67 0 11 0 88t0 04 analysis Post explant one flow cycle after was observed flow drug was present damage to the flow restrictor preventing indicated No catheter of the pump to the outlet from the reservoir delivery were reported complications device other of the during with hepatoxicity FUDR therapy All dogs receiving presented catheter to a refined This was attributed placement investigation of the with a majority consistently which led to drug infusion technique liver were version two 2 Pumps of the modified On November 9 1992 During hounds for 105 days each one in each of 2 mixed breed implanted every 3 to 4 of each pump were accessed the bolus chambers time this with 30 Each pump was also refilled bolus needle a special days using every 14 days using a 22 gauge non saline ml of heparinized 1000 U ml and 16 pump of 65 bolus accesses A combined total needle coring for each pump observed flow rates The average were performed refills ml day and 1 80 0 22 ml day 1 29 1 9 ml day were 1 55 0 20 range 1 were observed events adverse The following ml day 1 3 2 0 range of time At the and dislogdements occlusion 2 catheter pump pump No edema was were free of infection both pump pockets explant reported the Pump was considered results Based on these in human subjects implantation C Clinical safe for Studies was conducted A clinical evaluation of the pump for the and reliability fluids associated Description reasonably of Patient to assess delivery the ease of use of FUDR and other safety Population were enrolled in the study at nine Eighty two 9 82 patients and Approximately equal numbers of males investigational centers 46 with a were included ranging in age from 30 to 84 years females 36 cancer Patients had metastatic liver mean age of 61 years Patients were excluded with extrahepatic metastases unless the metastases could be surgically irradiated removed or effectively Pump Experience 12 with 64 Model 3000 pumps were implanted 62 Sixty two patients These 15 1991 April and 1988 1 June between version initial Average months 1 069 35 of a total for patient were implanted During follow up 16 to 1688 was 525 days range follow up were access performed 286 bolus and procedures pump refill of the pumps patient 1 950 with 21 Model 3000 Pumps With Bolus were implanted Twenty 20 patients The 15 1995 and February 15 1993 December Valve between Safety 3000 Model of the version pump initial the between difference principle of incorporation was the Valve Safety Bolus With Pump and the Model 3000 modification This fluid bolus the in valve safety pathway the bolus of the Pump flow operation on the continuous effect had no observable months 139 99 of total a for patient These pumps were implanted During 36 to 400 was 250 days range follow up Average patient were access bolus 47 and procedures 285 pump refill follow up performed of 1 209 34 over a total was gathered patient Combined pump experience two Two thousand days 433 was follow up Average patient months access bolus 333 and procedures thirty five 2 235 hundred pump refill were performed Pump Performance rates based on complication of the Pump was assessed and efficacy Safety drug to therapy response Objective and in vivo flow rate measurements as supportive were evaluated rates survival and patient data toxicity information 1 In Vivo Flow Rates cycle of FUDR and heparinized on off of a 14 day consisted FUDR therapy or grade 4 was evident tumor progression unless and continued saline at of each pump were measured In vivo flow rates was noted toxicity and flow accuracy determine to were analyzed The data refills pump over flow rates elevated early Pumps exhibited over time consistency to elevated This has been attributed few pump cycles pump the first interval for average A 95 confidence temperature post implant pocket in viva an average Pumps exhibited normalized flow was constructed response Based on patient 16 1 of 1 9 error flow rate SD was not variation data this and drug toxicity rates survival Measurement of FUDR for the delivery significant considered clinically variation in flow the to contributor as the largest was identified error were to estimated viva rates flow of in errors Measurement rate error measurement error The average than 200 to from 14 range greater than 50 was was greater error where the percent flow cycles excluding 24 5 as estimated using the van Neumann over time was evaluated Pump flow consistency Of the fluctuation flow rate for randomness in to test statistic von Neumann using the were evaluated 81 pumps pumps implanted failures device due to early Two pumps were unevaluable statistic 13 85 expiration due to patient One pump was unevaluable no flow ie was unevaluable 1 and to the device unrelated pump implant after shortly Fourteen implant after shortly thrombosis artery due to an hepatic significant of the 81 evaluated pumps showed a statistically 17 3 down fashion up and an excessive in in flow rate either trend long term on Based drop rapid a in decline ending or in a form of steady clinically were not considered trends these outcomes clinical of FUDR for the delivery significant Complications 2 observed and complications reactions Adverse Flow Operation Constant bolus path 2 study are as follows the clinical pump failure during cannula erosion cannula 1 dislodgment cannula 2 occlusion 4 1 contaminated occlusion cannula 2 pump reservoir leakage 2 thrombosis artery hepatic response febrile 1 3 drug extravasation infection 1 infection pump catheter 1 pump pocket 1 injection bolus seroma 1 hematoma recurrent 1 dislodgement 4 FUDR and occlusion 1 catheter error error training 1 partial or related as device the events Table 1 separates toxicity 43 with the initial the experience and compares related user procedure is Drug toxicity version of the modified version of the Pump to that below addressed Device Version Initial Complication Related User Procedure Related Overall Table 1 Complication rates are given of Pump Modified Version Pump 0 0 18 2 12 2 2 12 25 as percent of complications per B3 patient month In each study in the clinical early failures occurred Two 2 device flow was initiated before of these cases a pump was implanted proper This problem was corrected neither Subsequently pump flowed in vivo of combined with the addition to the flow restrictor by a modification Instructions for Use more precise the injection of an due to stoppage of flow after One pump was explanted Post explant bolus NAA through the HAPS imaging agent TCC 99 pathway within analysis of this pump found the pump to be operating from collected the catheter masses However specifications particle were was present The particles catheter occlusion suggested a partial and found to be denatured analyzed protein clinical study the in this Although not reported Bolus Path Access Inadvertent in another study was observed Bolus of Drug adverse event version of the Pump Since the investigating the use of the initial Valve Bolus Safety no events has been modified to incorporate the Pump observed type have been of this 14 Bolus Error Training Injection event labeled one adverse However of the version modified with the use of the has been observed Error non coring 22 use of a the inadvertent gauge involved This event Pump to be drug The injection a bolus to perform when attempting needle of the pump reservoir was added to the contents bolused with associated rates of the complication a comparison Table 2 provides Pump and the of the version in the initial the use of the bolus pathway of the Pump version modified version Initial of Pump compl access 0 0 User Procedure Related 0 35 2 13 Total 0 35 2 13 Device Table 2 Version Modified of Pump compl access Bolus Related Path Access Complication Rates study in the clinical reported rates and complication events The adverse available commercially with other observed to events are comparable for the indications are acceptable These event rates implantable pumps for use of the device 3 Overall Objective Response to Therapy 1 as follows was graded to therapy objective response The overall of tumor evidence of all clinical disappearance remission complete CR evaluation and biochemical scan x ray examination on physical greater in the sum of the 50 decrease 2 partial remission than 1 month PR lesions for of all measured diameters of the perpendicular products or of any lesions in size increase no simultaneous 1 month than greater 50 decrease stabilization lesions may occur 3 SD of new appearance and for greater than two months in measurable disease or 25 increase or the measurable disease 25 increase in 4 progression PD using 71 were evaluable Of the 82 patients of new lesions appearance due were unevaluable response criteria Eleven patients the objective cannula thrombosis erosion hepatic artery to complications eg 2 No patients or less than 4 months follow up no FUDR therapy 5 4 or 8 5 Seven complete remission as defined exhibited 7 patients or 30 5 exhibited Twenty five response showed a partial 25 patients exhibited Thirty nine or 47 6 disease stabilized 39 patients disease progression 4 Drug Toxicity the drug Table 3 summarizes These rates clinical study similar implantable pumps related toxicity are comparable 15 7U reported events to those reported during for the Hepatic Enzymes Elevation of Patients Pump Biliary sclerosis Diarrhea Gastric Ulcer Disease Elevated Bilirubin Initial Version 62 42 15 2 0 3 Modified Version 20 20 0 5 0 0 Table 5 3 Rates Drug Toxicity Rates given events per patient Rates Survival in the rates survival patient in four collected 4 published the data collected demonstrates in the literature that reported 1 year and 2 year Table 4 compares data study with survival clinical The comparison studies clinical with study is consistent clinical 1 yr 12 24 mo Patient Implants HAI Study 2 60 23 M3000 modified version 20 na na MSKCC 162 60k 25 NCOG4 143 60 30 64 85 44 162 61 20 Table 4 Patient Survival the 1 62 France in 25 36 mo M3000 initial version NCI XI as percent Data CONCLVSIONS DRAWNFROM STUDZES is valid Application Approval in the Premarket The information provided the Model that reasonable assurance and provides evidence scientific Valve is safe and Pump with Bolus Safety Flow Implantable 3000 Constant tests II The in vitro stated in Section for the indications effective of the device extent the specifications to a reasonable substantiate is the device demonstrate Various and animal tests laboratory of the clinical The results and non toxic non pyrogenic biocompatible for the stated the device is safe and effective indicate studies rates reported survival for use Drug toxicity and patient indications to those are comparable when using this device for its indications implantable available for other commercially reported in the literature study in the clinical of the Two to three percent patients pumps to the use of the that appeared to be related complications experienced device investigational The combined results the requisite provide device for the stated of the laboratory assurance of the indications 16 7 animal and clinical testing and effectiveness safety of the XI PANBL RECOMMENDATIONS of The General Use Device Section and Personal Hospital The General and the safety Panel met on March 5 1991 to consider Devices Medical version Pump initial of the Model 3000 Implantable effectiveness The panel the Model conditions XIII to recommended 3000 Implantable of version CDRH that the PMA for the original with approvable Pump be considered FDA DECISIONS to the in a letter recommendation with the Panel s The FDA disagreed was based in part on This decision 22 1991 dated April applicant of accuracy flow rate data to the clinical related issues outstanding and the marketing data drug stability data function the Pump bolus Pump the of history thereafter occurring Shortly events FDA became aware the use of the of reports Pump of bolus inadvertent the met with FDA and presented the applicant 1992 Valve Safety Bolus the incorporate to to the Pump On July 27 modification On December 1 the use of the On January with 29 amended the the applicant 1994 the Pump of version modified 1996 FDA issued letter an approvable of the for the selection A justification statistical the van Neumann during applied of the von Neumann statistic and completion not yet evaluated Clarification sterilization 4013 the MA with clinical data requesting criteria exclusion of the pumps analysis for pumps calculations and and packaging Needle Cat I Kit and Refill information of the pump packaging Bolus for the Special information 4009 Needle Arrow Non Coring Cat 4 Cat 7001 3 Information components 4 A revised following a b status Refill on the marketing in the contained copy of changes the Instructions and processing Kit Cat 47001 For Use to clause the following for their recognized and long life biocompatibility 17 of the include use statement of the investigational removal of the prescription and inclusion 812 5 a where appropriate CFR 801 109 b 1 of removal materials on the 21 CFR statement under DESCRIPTION of high degree and 21 the use of which explain of instructions the inclusion relate to the on page 19 and how they provided graphs flow rate specified on the pump label arterial C Removal of the Contraindications statements d 5 section Patient Selection the section to include I be used with added FUDR should hepatic or renal with impaired ii patients capable therapy of the long term safety a postapproval study to confirm modifications of the design and labeling effectiveness implemented to address early reports of inadvertent administration of drug product to patients and of the following bolus b a postapproval study to establish the compatibility between infusates materials the indicated and the device over repeated for a minimum exposure of 6 pump refills period months C a postapproval study to establish long term changes in flow variation accuracy under controlled and consistency ie laboratory conditions applicant amended the PMA satisfactorily requested and agreeing to comply with and to conduct the listed postapproval On September 13 1995 the applicant s inspected and found to be in compliance Practices GMP regulations XIV the in patients and caution function Conditions On February 6 1996 the suppling the information Conditions of Approval On of beyond an area with known disease extending for systemic of infusion should be considered and with other agents chemotherapeutic with or suggested revision Concurrence and agreement to conduct the Approval a and revision following the 3 8 I I FDA issued an approval the studies manufacturing facilities had been with the Good Manufacturing order to the applicant APPROVAL SPECIFICATIONS The approval specifications conditions of approval are described and with addition in Section XIII of the following and in the FDA restricts the sale distribution and use of this device to use in accordance with 21 CFR 801 109 within the meaning of prescription section 520 e of the Federal Food Drug and Cosmetic Act the act under the authority of section 515 d 1 B ii of the act FDA has also determined to ensure that the safe and effective use of the device 18 F1 the meaning of section within restricted is further the device that as insofar 1 515 d 1 B ii section of authority the under 520 e of that apply to the training specify the requirements the labeling as the sale insofar and device 2 the may use who practitioners of the and r 502 q sections and use must not violate distribution act 19 1 2 3 4 Distribution J Von Neumann to the difference successive 367 395 pp Von Neumann ratio of the Math Statist References of the variance of the ration Ann Hath A further remark concerning J difference successive mean square 86 88 13 1942 pp mean square 12 Statist of the distribution to the variance 1941 the Ann J Oderman Botel N B Geller Reichman J Daly Kemeny N in fluorodeoxyuridine of infusion patients systemic or Intrahepatic Red Ann Intern carcinoma from colorectal metastases liver 1987 107 459 465 P with trial randomized PH A prospective PD Sugarbaker Chang AE Schneider chemotherapy 5 fluorodeoxyuridine continuous versus systemic regional 206 685 Ann Surg 1987 metastases liver of colorectal the treatment 693 of trial A randomized M et al Friedman R Stagg in floxuridine intraarterial hepatic versus intravenous the northern liver the to metastatic cancer with colorectal 1989 7 1646 1654 ecol J Clin oncology group trial 5 Hohn D continuous patients California 6 J Laplance Escat JM Olivier PH Hay J M Rougier chemotherapy trial of intra hepatic multicentric A controlled metastases liver for colorectal treatment standard palliative DISCO 1990 9 104 Proceedings 20 A et al IHC vs of in