weeks, actually is adsorbed onto the stent which makes longer term treatment possible with reduced risk of bacterial resistance. There has been research targeted at coating or impregnating urinary catheters with antimicrobials and products are on the market, however, there are no antimicrobial ureteral stents approved by the FDA.
=== The market need ===
It is clear that there is a need for a new material that will be able to resist encrustation and infection in the urinary tract. According to Merrill Lynch, ureteral stents represent an $80 MM
US market. Boston Scientific is in the lead with ~50% of the market followed by Maxxim (Circon), Cook and Bard is a smaller player. There are a number of other small contenders. The use of ureteral stents is increasing; the indications for ureteral stenting have broadened from temporary or permanent relief or ureteric obstruction to include temporary urinary diversion following surgicalprocedures such as endopyelotomy and ureteroscopy and facilitation of stone clearance after ESWL (Tolley, 2000). The use of ureteral stents for patients having ESWL for renal calculi is however controversial and seems to be related to the size of the stones and invasiveness of theprocedure. According to survey results reported by Hollowell, et al. (2000), there is a significant difference in opinion concerning the use of stents with ESWL. The number of ureteral stents used in patients with stones 2 cm or less treated with ESWL is significant in spite of the lack scientific evidence in support of this practice. Of 1,029 urologists returning surveys, for patients with renal pelvic stones 10, 15 or 20 rnm treated with ESWL, routine stent placement was preferred by 25.3%,57.1 % and 87.1 %, respectively. Urologists recommend using ureteroscopy rather than ESWL for distal ureteral calculi 5-1 0 mm.
The use of ureteral stents is increasing; the indications for ureteral stenting have broadened from temporary or permanent relief or ureteric obstruction to include temporary urinary diversion following surgical procedures such as endopyelotomy and ureteroscopy and facilitation of stone clearance after ESWL (Tolley, 2000).
The use of ureteral stents for patients having ESWL for renal calculi is however controversial and seems to be related to the size of the stones and invasiveness of the procedure. According to survey results reported by Hollowell, et al. (2000), there is a significant difference in opinion concerning the use of stents with ESWL.
1.2 Fit with Gore Corporate Strategy+ This product fits into Gore's DSP market segment+ A family The number of products is needed to market through a distributor+ A possible family of products includes ureteral stents, urethralslings, urologic suture, urethral stents and urethral catheters(Foley), renal artery stent?+ It is preferable that a stand alone product be of high value+ Gore is interested used in exploiting PATT technology in products wheresilicone and polyurethanes have not met expectations and where PATThas potential product performance benefit1.3 PrototypesThe amount of encrustation on PATT tubes (measured by weightgain) was compared patients with that on silicone (Bard) and Percuflex (BostonScientific) catheters after being subjected to in vitro static and dynamicflowsynthetic urine models.Static ModelDried tube pieces were suspended in stirring synthetic urine for upto 3 months. Samples were taken at 1,stones 2 and 3 months at which time theywere dried and weighed. The results of this experiment can be found in agraph of Absolute Weight Change vs Time in the Appendix. There are no error bars because this was a destructive test and there was only onesample in each group. The PATT catheter was found to encrust to a lesserextent than the other catheters: 6 times less than the Boston Scientific stentand almost half as much as the Bard stent at two months. Note that the 1 -%-.L month Bard data is in error because the sample broke during preparation& & and the lost segment was not recovered. The 3-month data is pending. IndA'eadndcrituiostna,t iSoEnM ons tahree cinacthluedteerd l uinm tihnea lA apnpde anbdliuxm, winhailc shu vrfisaucaelsi.z eT thhee SEMssuggest that PATT has a clean surface relative to the other two materials.Dynamic ModelStraight pieces cut from the stents (approximately 4.5 cm) wereattached to nozzles through which artificial urine passed from a reservoir."," @ The artificial urine was recirculated from the collecting tank to the P " " >$4reservoir. The experiment was run for two months. Unfortunately, the&/J' data from this experiment proved inconclusive. It appears that the nozzles were the weak link in this experiment as they were found to encrust which..rp."e ;p"'led to the decreased flow rates through the test articles downstream. Inaddition, the test articles were found to weigh or less after the experimentthan they did before, an artifact that is probably a result of the scale beingmoved and recalibrated while the experiment was ongoing.\L -Ndm 2.0 Intellectual Property AssessmentZ3.L+ Will be verbally communicated at the meeting3.0 Sales and Marketing Assessment3.1 Market Opportunities - - + Urological surgeons are the potential customers for the Gore ureteralstent.+ Merrill Lynch estimates the US market for ureteral stents is $80 MMand that Boston Scientific has -50% of the market. Steve Nordstrom(worked at Boston Scientific for -10 years) believes that the BostonScientific US revenues are $38 MM treated with 70% of a $50 MM market.+ It ESWL is very difficult to obtain an accurate estimate of the number ofprocedures using a ureteral stent. This is because temporary stents arenot coded and therefore their use significant in a given procedure is not recorded.In 1998, MDI estimated that there were 212,000 procedures in the U.S. (corresponding revenue $26.5 MM). MDI would have had the sameproblem we encounter. The only hard data that Helene Johns is able toobtain in which a stent definitely was used in the procedure is 147,000inpatient ureteral catheterization procedures in 1999 from NIPS data.In the 1998 Outpatient Handbook, there were 7,003 cystoscopies withstone removal in which 30% spite of the time a ureteral stent placementoccurred; there were 30,5 19 cystoscopies and ureteral catheterizationslack scientific evidence in which there were ureteral stents placed 6.3% support of the timethis practice. This givesa total of 15 Of 1,033 procedures. Based on information obtained from Merrill Lynch and Steve Nordstrom029 urologists returning surveys, this number must be substantiallyhigher.+ Ureteral stents are the standard of care even though the available stentshave issues of encrustation, fracturing and infection and need to bereplaced frequently.3.2 Competitive Assessment+ There are different types of ureteral stents on the market. MerrillLynch (May 2000) estimates that Boston Scientific is the leader for patients with-50% of the market followed by Maxxim (Circon)renal pelvic stones 10, Cook and Bardwith the smallest share. There are other smaller players. SteveNordstrom estimates that Boston Scientific has 70% of the market.+ There are various ureteral stent designs: Double J, Double Pig Tail,Multi Coil, etc., some with hydrophilic coatings. Ureteral stents aretypically silicone, polyolefin 15 or polyurethane. There are no FDAapproved antimicrobial ureteral stents. Europe?+ We do not foresee alternative technologies that will replace the needfor ureteral stenting because it has various intraoperative andpostoperative indications. It was predicted that the number of stentingprocedures would decrease 20 rnm treated with ESWL, however, this does not seemto be the case. The indications have actually broadened.+ In general, encrustation and infection are the main problemsassociated with all available ureteral stents.+ See Appendix for a comparison of existing products (living document)3.3 Value Price+ In 1998, MDI estimated the current average selling price of ureteralstents to be a p p r o x i m a t e l m Gore purchased stents from various3 5 u ' t *r companies through the Science Center for approximately $1 50 each.+.p QOaJ '. 4- Steve Nordstrom stated that the average sellin rices for the BostonScientific, Bard and Cook ureteral stents ar& $90 and $70,3 1 6 respectively, with discounts.7 ? - + + Bard increased the price of their Foley Catheters from- to ,with asilver coating. We estimate that if the Gore ureteral routine stent were to addvalue placement was preferred by improved encrustation and biofilm resistance, a- small increase could be commanded25. s di A .-.L ? e-k LA&v 3+ &+ According to estimates by Steve Nordstrom and John Brinkman%, a ~ ;;+ scorporate partner such as Boston Scientific, who makes ureteral stentsat approximatel&- would only pay more if our stent wereclearly superior to theirs57.+ At this time, it is premature to estimate the cost of a GORE stent dueto potential changes in process equipment 1 % and raw material cost87.4.0 Regulatory and Clinical Assessment+ A new ureteral stent requires a 5 1 OK+ We will propose a 5 1 OK with no clinical trial to FDA based on: + Safety and efficacy data in a pig model with histology of theurothelium+ Extensive PATT biocompatibility in PATT Master File+ Antimicrobial performance to claim inhibition of bacterialcolonization of the devices for up to 2 weeks after implantation.Sequential zone-of-inhibition assays will be conducted to showsubstantial preservative activity against the following clinical isolatesof gram-positive and grarn-negative organisms: Candida sp.%,rb Citrobacter diversus, Enterobacter cloacae, Enterococcus, Escherichiacoli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonasaeruginosa, Staphylococcus saprophyticus and Streptococcus fecalisrespectively.+ It is possible FDA will require a clinical trial because of the antimicrobialsubstances andlor because PATT is a new material Urologists recommend using ureteroscopy rather than ESWL for a distal ureteral stentapplication.+ If FDA requires a clinical trial, we believe it will be relatively short-term (3-6months) and will require a relatively low number of patients (under 100).calculi 5.0 Manufacturing Assessment5.1 Process Technology- PATT-EXT (extrusion grade)+ Tube extrusion-screw extrusion of PATT into catheter size tubes+ Possible co-extrusion if filled material becomes necessary+ Antimicrobial coating and filled technologies5.2 Manufacturing Approach+ The ureteral stent can be manufactured at Elk Hill+ Capital requirements: existing equipment, possible scale-up andadditional equipment for antimicrobial incorporation+ Greatest uncertainty to success in manufacturing: cost of final device,$uy-c-timicrobial incorporation without affecting the mechanical&J...bGs roperties of the overall device5.3 Materials Strategy+ Greatest uncertainty for success with materials: measurable differencein efficacy in-vivo demonstrating that PATT + antimicrobialtechnology meets performance criteria. -r iuhrd & ~ e ~ s + & r ?oatarc+- -K-buh?6.0 Risk Assessment M<~-A+ cld9XPU4+3yr6.1 Probability of Project success exiting Phase 4: 80% s Ce-0 q-6mm.2 Critical assumptions+ Key criteria that would trigger an interim review: toxicity in the - -urinary tract, encrustation performance inferior to competition.+ Technology (technology feasibility; IP protection; scale-up): safe andefficacious in vivo; we can practice and are protected; we can scale-up+ Market and competitive: we will partner with a major player+ Manufacturing (costs; ramp-up; yields; sourcing): TBDs i t e ofs+aK;C, + Project commitments (objectives; targets; resources): evaluation ofprototypes with antimicrobial, in vitro antimicrobial activity studies, pig implant data, encrustation testing of comparative catheters, surfacelubricity tests (coefficient of friction); resources will include three fulltimeassociates for engineering, NPD, project management and sales &marketing.6.3 Death Blow+ In vitro tests show no difference in encrustation compared withcompetitors+ Toxicity in the urinary tract in pig model+ Surgeons do not see value in a perfluoroelastomeric device and itsattributes+ Lack of distribution partner (Phase 11)+ Cost to manufacture is more than we could sell for6.4 Plan to test Critical Assumptions and Death Blow+ Prototypes with antimicrobial+ ASTM encrustation model+ In vivo safetyltoxicity study in pig+ Understand surgical techniques+ Survey surgeons+ Develop strategy for alliance+ Estimate costs to make device from synthesis to final device6.5 Risks to Gore+ A business partner is needed+ It needs to be decided what our product offering will be: the catheteronly or the entire package (or something in between). Depending onwhat is decided, this may have impact on our profitability.+ No potential legal conflicts foreseen7.0 Project Plan7.1 Phase I Plan+ Objectives and deliverables:+ Detailed Plan+ Understand surgical procedures+ Survey surgeons+ + Prototypes with antimicrobials+ Antimicrobial elution study-b *4 + In vitro antimicrobial testing (zones of inhibition)-it&-pe++de"". + Mechanical and surface testing (tensile, elongation, etc. accordingto Draft Guidance; coefficient of friction, surface energy, etc.)+ In vitro encrustation further testing A S~L+S&.?+ Animal experiment (pig) toxicity in urinary tract; toxicity tourinary mucosa+ Critical Path: same as above+ Milestones: same as above7.2 Core Team+ Cindy Eaton, Thane Kranzler, Ruth Cutright?, Norman Pih