Margin Probe® Radiofrequency Spectroscopy System PDF

® MARGIN PROBE Proven to reduce re-excisions in breast cancer Margin Probe® Radiofrequency Spectroscopy System Identifies, in real-time, positive margins by detecting microscopic residual cancer and DCIS at the surface of excised breast tissu...

® MARGIN PROBE Proven to reduce re-excisions in breast cancer Margin Probe® Radiofrequency Spectroscopy System Identifies, in real-time, positive margins by detecting microscopic residual cancer and DCIS at the surface of excised breast tissue, enabling immediate action by the surgeon, thereby MARGIN PROBE reducing the need for re-excision surgery. Did I get it all? Current margin assessment methods cannot fully address need APPROVED Gross Assessment, Specimen X-Ray Cannot palpate/visualize microscopic invasive cancer nor DCIS Low sensitivity for ILC Frozen Section Difficult due to fatty nature of breast tissue May add significant time to procedure Full Cavity Shave Can compromise cosmetic outcomes due to volume of healthy tissue removed Thinner shaves to manage tissue volume can result in reduced success clearing final margins Re-excision impacts everyone t Increased ca V) !.... Disappointment of..'! Tremendous cost V) (1) telling patient to healthcare financial burden C ·- 1J V) Increased "I didn't get it all" system ·-(1) !.... Decreased patient complications Delays adjuvant > satisfaction >- (1) Average $16k/procedure 0 0 Compromises IORT 0 Not aligned with a... treatment a... a... !.... Poor cosmesis and oncoplastic shift from volume procedures to value 1 Metcalfe LN, Zysk AM, Yemul KS, et al. Beyond the Margins-Economic Costs and Complications Associated With Repeated Breast-Conserving Surgeries. JAMA Surg. 2017;152(11):1084-1086. How does MarginProbe® work? As tissue becomes malignant, its cellular morphology and electrical behavior change I o.~c--------+--l---,,L--------------+-+~ ~--+---4 0.4 r - - - - - - + - - - - - - + - + - - - - - J ~ - + - - - - - + - - ---------+ !e2. 2::- 0.4~ - - - - - - t - -------,,'--j - - - - -- - - - -<. - - -~ -------j ·;; 0·3 r - - - - - - + - - -N - orm - a c+--- 1 l-----+-----+-----+----------' g 0.3 ~ -----+, 500 u 0 2007 2008 2010 2014 2015 201 6 2017 2018 2019 2020 2021 * *Jan-Mar MarginProbe®. Do it once. Get it all. MARGIN PROBE Dilan Medical Technologies Inc, 12050 Jefferson Avenue, Newport News, VA 23606 877-GO-DILON - www.dilon.com MRK-00156 Rev 1 ! These%scripts%below%were%extrapolated%from%a%series%of%role4playing%conversations%we%conducted%internally,%looking%at% various%potential%pre4sale%questions.%% ! Surgeon(Meeting( ! Q:#“How#does#it#work?”# % A:!The!device!works!using!a!set!of!principles!that!have!been!extensively!studied!and!published! in!the!electrical!engineering!literature!for!the!last!30!years.!!When!cancerous!processes!start!to! happen!in!cells,!there!are!a!number!of!biological!effects!we’re!all!familiar!with! DeCpolarization!of!the!cell!membrane! Increase!in!vascularity! Changes!in!the!nuclear!morphology! Each!of!these!changes!affects!the!way!cells!respond!to!a!nearby!electric!field.!!Using!a!technique! called!RF!Spectroscopy,!the!MarginProbe!applies!a!series!of!electric!fields!at!different! frequencies,!and!measures!the!reflection.!!That!reflection!is!different!for!cancer!vs.!healthy! tissue.!!This!effect!is!based!on!properties!inherent!to!the!tissue,!and!doesn’t!rely!on!any! injection!or!tracer.!!You!then!use!the!MarginProbe!intraCoperatively!by!applying!it!to!your! Lumpectomy!specimen!and!the!console!will!give!you!real!time,!instant!feedback!if!it!senses! cancer,!or!DCIS!on!the!margin.!!You!can!then!take!additional!shavings!as!needed!based!on!your! clinical!judgment!and!the!MarginProbe!readings.! ! Q:#“How#accurate#is#it?”# ! A:!The!sensitivity!depends!on!how!much!cancer!is!present!on!the!surface!of!the!lumpectomy.!! For!larger!amounts!of!cancer,!a!few!millimeters!in!size,!the!sensitivity!is!100%.!!The!big! difference!between!the!MarginProbe!System!and!current!techniques!is!that!the!sensitivity! remains!very!high!all!the!way!down!to!a!sensitivity!of!50%!for!a!half!a!millimeter!DCIS!feature,! i.e.!a!single!milk!duct!with!DCIS!in!it!.!!The!specificity!is!70%.! ! ! ! Reference%Pappo%study! ! Q:#“Does#it#work#on#DCIS?”# ! A:!It!does.!!We!hear!this!question!a!lot!from!surgeons!because!of!the!challenges!DCIS!presents.!! I!assume!you!have!these!same!challenges?!!We!have!3!studies!that!looked!at!MarginProbe’s! performance!as!it!relates!to!DCIS.!!Two!analyzed!all!cancer!types!and!one!analyzed!DCIS!only! patients.!!What!the!research!shows!is!that!MarginProbe!performs!equally!as!well!for!all!cancer! types!and!significantly!reduces!reCexcisions!rates!in!DCIS!only!patients.! ! Reference%Pappo,%Blohmer%and%Thill%studies% For$Internal$Use$Only$–$Not$For$Distribution$ ! ! Q:#“The#FP#rate#is#high#in#the#data,#that’s#not#accurate#enough.”# ! A:!The!specificity!is!70%,!meaning!the!false!positive!rate!is!30%.!!This!number!is!a!little! difficult!to!put!in!context,!since!there!are!5C8!measurements!on!each!of!the!six!margins.!!In! order!to!assess!the!impact!of!false!positives!on!the!tissue!volume!removed,!we!looked!at!the! tissue!removed!in!each!of!our!randomized!trials.!!On!average,!when!MarginProbe!was!used,! there!were!two!additional!margins!shaved!per!patient.!!After!all!surgeries,!this!resulted!in!a! difference!of!less!than!10cc,!or!2!tea!spoons.! ! High!specificity!is!important!to!avoid!“overtreatment”!(excessive!additional!procedures,! such!as!biopsies,!etc.)!in!a!screening!environment.!!Intraoperative!margin!assessment!is! NOT!a!screening!test! ! High!sensitivity%is!important!to!avoid!“undertreatment”.!The!impact!of!specificity!needs!to! be!evaluated!per!the!specific!application.!!In!intraoperative!margin!assessment,!the!impact! of!specificity!is!shown!in!tissue!volume.! ! ! Q:#“How#does#the#data#look#when#applied#to#the#new#SSO#guidelines?”# ! A:!Have!you!adopted!those!guidelines!for!all!procedures?!!The!reason!I!ask!is!that!in!our! discussions!with!surgeons,!we!are!seeing!a!variety!of!answers.!!While!many!have!adopted!the! no!tumor!on!ink!definition,!many!are!still!using!1C2mm!for!DCIS!or!instances!of!multiCfocal! disease.!!What!our!data!shows!is!that!regardless!of!whether!you!use!1mm,!2mm!or!no!tumor! on!ink,!we!see!50C60%!reductions!in!reCexcisions.!!In!fact,!when!we!extrapolated!out!our!FDA! Pivotal!Trial!data!(which!used!1mm!for!a!positive!margin),!we!showed!that!even!when!using! no!tumor!on!ink!as!the!definition!of!a!positive!margin,!we!improved!the!positive!margin!rate! from!13%!to!6%!C!equaling!a!53%!improvement.! ! ! ! ! Reference%the%Gittleman%Poster% ! Q:#“My#reFexcision#rate#is#very#low,#I#don’t#need#this!”#(Assumptions%here%are%that%they’re%in% the%10425%%range.%%If%they%truly%believe%they%are%in%the%548%%range%(unlikely,%and%very%rarely% reported),%they%may%not%be%the%right%target)# A:! 1. %Dr.,!I!hear!this!from!surgeons!quite!often.!!We!know!that!nationally,!it!is!well!documented! that!the!average!reCexcision!rate!is!around!20C25%,!with!some!studies!going!40%!or!higher! in!DCIS!patients,!so!I!applaud!you!on!being!well!below!the!national!average.!!What’s! interesting!in!our!data!is!that,!regardless!of!your!starting!reCexcision!rate,!we!have! repeatedly!shown!reductions!of!50C60%.!!We!have!published!data!showing!reductions!from! 12%!to!4%!and!from!12.7%!to!5.6%.!!If!we!showed!you!a!50C60%!reduction!in!your!reC excisions,!would!you!use!the!MarginProbe!in!your!practice?! For$Internal$Use$Only$–$Not$For$Distribution$ ! ! Reference%Allweis%Study%and%Sebastian%Poster% ! 2. Dr.,!I!certainly!can!appreciate!that.!!Do!you!track!your!reCexcision!rate!as!part!of!a!quality! measure!for!the!Breast!Center?!!What!is!your!specific!rate!currently!and!do!you!break!out! DCIS!only!cases?!!The!reason!I!ask!is!that!when!we!discuss!the!challenges!of!DCIS!with!our! surgeons,!we!get!a!consistent!response!that!these!are!the!cases!where!the!MarginProbe!can! provide!even!greater!value!for!you.!!Because!you!can’t!see!or!feel!DCIS,!the!MarginProbe’s! ability!to!detect!these!microscopic!cancers!allows!you!to!be!much!more!confident!you!have! addressed!all!of!the!positive!margins!on!your!Lumpectomy!specimen.!!How!often!do!you! see!DCIS!component!in!a!case!that!was!diagnosed!as!IDC!in!the!biopsy!preCop!imaging?!! Additionally,!we!find!quite!often!that!we!are!able!to!find!DCIS!on!cases!that!otherwise! would!have!been!undetected!until!final!pathology.!!(Goal$is$to$get$agreement$that$DCIS$ presents$a$greater$challenge$and$could$be$your$path$to$them$becoming$a$believer$or$ otherwise$admit$they$have$a$problem$with$their$ego$intact).! ! 3. Oncoplastic$surgery:$$Dr.,!you!mentioned!that!you!routinely!utilize!an!oncoplastic! approach!for!many!of!your!breast!conserving!patients.!!This!is!a!subset!of!patients,!where! we!find!additional!value!with!the!MarginProbe.!!!While!your!reCexcision!rate!for!these! patients!may!be!low,!when!there!is!a!positive!margin,!these!patients!very!routinely!have!to! convert!to!a!mastectomy!–!correct?!!If!you!are!able!to!reduce!the!positive!margin!rate!in! these!patients,!do!you!think!there!would!be!added!value?! ! 4. IORT:$$What!is!the!impact!of!a!positive!margin!with!an!IORT!patient?!!The!reason!I!ask!is! that!even!with!an!overall!low!reCexcision!rate,!there!is!typically!heightened!concern!with! these!patients!because!they!are!waking!up!from!surgery!anticipating!that!their!surgery!and! radiation!are!complete.!!Having!to!tell!the!patient!they!need!to!go!back!for!additional! surgery!and!then!followCup!radiation!certainly!is!a!demoralizing!conversation,!wouldn’t! you!agree?!!!!! ! Additional$Discussion$if$the$surgeon$routinely$does$whole$cavity$reshaving:$ ! 5. Maintaining!a!balance!between!a!good!oncologic!procedure!and!good!cosmesis!certainly!is! the!goal!for!breast!conserving!surgery.!!Many!of!our!surgeons,!whether!they!were! traditionally!utilized!routine!full!cavity!shaving!or!took!larger!specimens,!have!found!that! by!implementing!MarginProbe!into!their!practice,!they!have!been!able!to!maintain!low!reC excision!rates!while!reducing!their!overall!tissue!volume.!!Would!being!able!to!reduce!your! overall!tissue!volume!taken,!while!maintaining!a!low!reCexcision!rate!provide!value!to!your! patients?! ! ! ! ! For$Internal$Use$Only$–$Not$For$Distribution$ ! Q:#Is#there#reimbursement?# ! A:!Yes,!there!is!both!a!hospital!and!physician!reimbursement!component!to!the!MarginProbe.!! The!key!element!to!remember!with!the!MarginProbe!is!that!it!is!billed!as!an!adjunct!procedure! to!the!Lumpectomy!and!this!automatically!separates!the!MarginProbe!from!most!other! products!you!might!use!in!the!OR.!!For!example,!if!you!were!to!use!LigaSure!in!your!case,!the! added!cost!of!the!device!is!added!into!the!costs!for!the!Lumpectomy!procedure.!!Because!we! bill!the!MarginProbe!as!an!adjunct!procedure,!it!opens!up!a!pathway!for!possible! reimbursement.!!We!use!CPT!19499,!which!has!a!published!Medicare!rate!of!approximately! $2200.!!When!billed!as!an!adjunct!procedure,!that!rate!would!be!reduced!by!50%,!so!the! reimbursement!would!be!approximately!$1100!–!which!covers!the!most!of!$1200!cost!of!the! MarginProbe!disposable.!!I!cannot!guarantee!reimbursement,!but!we!have!seen!consistent! reimbursement!from!Medicare!and!the!Private!payers.!!!The!reason!I!can’t!guarantee! reimbursement!is!that!each!hospital!is!going!to!have!a!variety!of!contracts!in!place!with!a! variety!of!payers.!!We!have!a!full!reimbursement!guide!and!a!fantastic!Director!of! Reimbursement!that!can!help!the!hospital!with!billing!and!reimbursement.!!We!support!the! entire!process!from!the!OR!through!potential!appeals.! ! As!far!as!the!physician!component,!the!19499!code!doesn’t!have!a!published!rate,!but! anecdotally,!many!of!our!surgeons!have!seen!an!average!of!+$200!for!the!physician!component! when!billed!appropriately.!! ! ! ! Reference%2015%Reimbursement%Guide% OR(Management(Meeting( ! Q:#“We#don’t#pay#for#evaluations?”# ! A:!Please!help!me!understand!what!exactly!you!are!referring!to!when!you!say!that?!!Are!you! saying!that!the!surgeon!needs!to!use!the!MarginProbe!a!couple!of!times!in!order!to!see!if! he/she!likes!it?!!Starting!a!MarginProbe!program!is!very!different!from!other!products!because! of!two!key!points.!!First,!part!of!the!consideration!for!longCterm!use!of!the!MarginProbe!is!a! financial!one.!!In!order!for!the!hospital!to!track!reimbursement,!it!needs!to!first!be!billed.!!In! order!to!stay!away!from!billing!Medicare!for!free!product,!it!is!best!to!pay!for!the!probes!and!to! bill!following!normal!procedures.!!The!other!aspect!to!the!reimbursement!is!that!it!takes! months!for!the!reimbursement!story!to!take!shape.!!It’s!a!long!process!that!we!will!work! directly!with!your!finance!team!on,!but!it!does!take!time.! ! Second!and!most!important,!the!surgeon(s)!want!to!be!able!to!track!the!clinical!impact!the! MarginProbe!will!have!for!his/her!patients.!!Our!goal,!consistent!with!multiple!published! studies,!is!to!reduce!the!surgeon’s!reCexcision!rate!by!50C60%.!!Currently!surgeons!don’t!know! when!they’re!going!to!have!positive!margins!and!need!to!take!a!patient!back!to!the!OR!for!a!reC For$Internal$Use$Only$–$Not$For$Distribution$ ! excision.!!If!they!did,!I!wouldn’t!be!here.!!Therefore,!if!I!were!to!give!the!surgeon!two!free! probes!to!use,!they!may!have!no!idea!if!the!MarginProbe!is!providing!clinical!value.!!We!could! save!two!reCexcisions,!or!we!could!have!no!clinical!impact.!!As!such,!we!ask!for!a!longer!term! commitment!to!give!the!data!more!power.! ! Q:#“I#can’t#add#$1000#to#my#procedure#costs.##That’s#more#than#we#make#on#a# Lumpectomy”# ! A:!I!certainly!understand!that!very!legitimate!concern.!!However,!the!key!element!to!remember! with!the!MarginProbe!is!that!it!is!billed!as!an!adjunct!procedure!to!the!Lumpectomy!and!this! automatically!separates!the!MarginProbe!from!most!other!products!you!might!use!in!the!OR.!! For!example,!if!you!were!to!use!LigaSure!in!your!case,!the!added!cost!of!the!device!is!added! into!the!costs!for!the!Lumpectomy!procedure.!!Because!we!bill!the!MarginProbe!as!an!adjunct! procedure,!it!opens!up!a!pathway!for!possible!reimbursement.!!We!use!CPT!19499,!which!has!a! published!Medicare!rate!of!approximately!$2200.!!When!billed!as!an!adjunct!procedure,!that! rate!would!be!reduced!by!50%,!so!the!reimbursement!would!be!approximately!$1100!–!which! covers!the!$1200!cost!of!the!MarginProbe!disposable.!!I!cannot!guarantee!reimbursement,!but! we!have!seen!consistent!reimbursement!from!Medicare!and!the!Private!payers.!!!The!reason!I! can’t!guarantee!reimbursement!is!that!each!hospital!is!going!to!have!a!variety!of!contracts!in! place!with!a!variety!of!payers.!!We!have!a!full!reimbursement!guide!and!a!fantastic!Director!of! Reimbursement!that!can!help!the!hospital!with!billing!and!reimbursement.!!We!support!the! entire!process!from!the!OR!through!potential!appeals.!!When!this!is!presented!to!the!Finance! and!Managed!Care!teams,!they!will!be!able!to!complete!an!analysis!from!a!different! perspective.! Purchasing/Finance(Meeting( ! Q:#“The#Dr.#said#there#is#a#code/reimbursement#for#MarginProbe,#I#don’t#believe#you!”# ! In$addition$to$the$Reimbursement$discussion$above,$here$is$a$more$technical$discussion$to$ walk$a$CFO/Finance/Reimbursement$Director$through.$ ! A:!The!MarginProbe!System!is!utilized!by!the!surgeon!intraCoperatively!to!perform! a%separate%procedure%following!the!lumpectomy!!!! ! As!such,!billing!would!be!as!follows:! For!the!lumpectomy!C!19301!–!pays!facility!on!national!average:!$2,166.79! For!MarginProbe!C!19499!–!Unlisted!Breast!Code!C!“Intraoperative!Assessment!Of!The! Lumpectomy!Margins!Using!RF!Spectroscopy!(procedure)! 19499!is!a!unique!miscellaneous!code!in!that!MEDICARE!HAS!ASSIGNED!to!an!APC! PAYMENT.!!19499!maps!to!APC0028.!!! For$Internal$Use$Only$–$Not$For$Distribution$ ! Both!19301!and!19499!procedures!map!to!the!same!APC!0028!with!a!Status!code!of!“T”! which!means!that!the!Medicare!Multiple!Reduction!is!applied.!!Thus,!the!primary!procedure! (19301!lumpectomy)!is!paid!at!100%!and!the!19499!IntraCoperative!Margin!Assessment! with!RF!procedure!is!reimbursed!at!50%.! Therefore,!the!total!allowable!Medicare!facility!reimbursement!for!lumpectomy!plus! MarginProbe,!using!the!National!Average!would!be!!$2,166.79!(19301)! +!$1,083.40!(19499).! ! Both!19301!and!19499!would!be!the!appropriate!codes!to!use!here,!as!the!surgeon!is! performing!2!unique!procedures,!the!lumpectomy!and!the!intraoperative!margin!assessment.! ! ! ! For$Internal$Use$Only$–$Not$For$Distribution$  Handling Clinical Objections False Positives “I’ve heard that Margin Probe has too many false positives.” Yes-there’s been a lot of discussion about false positives. Many surgeons I’ve talked to have commented on that. Many MarginProbe users thought that initially as well. But what they ultimately found after digging a bit deeper into their own practice data was that, by responding to the direction of MP, they took, on average, an extra 8-10cc more tissue volume, but they reduced their re-excision by half. In general, we know that surgeons will take an extra shave or two based on imaging or palpation. Breast conservation surgery always requires surgical judgement in order to find the proper balance between completeness of excision and acceptable cosmesis”. That is precisely how our algorithm was optimized, to find the balance between sensitivity and specificity so that all of the cancer is found and the least amount of tissue is removed When talking about false positives, if you think about it…FCS suffers from the same concern as there are more often than not, 6 false positives in that approach. The average FP rate reported throughout all of our papers is an average of 2 clinically insignificant shaves per case. Several of our peer reviewed papers discuss tissue volume comparison “Dammit!! I took that lateral margin on Mrs. Smith last week and I see here on this pathology report that it ended up being negative! I didn’t need to take that margin!” Introduce doubt regarding pathology by getting them to acknowledge the pathology process: I understand that MarginProbe is compared to final pathology as the gold standard. Are you familiar with how pathology processes the specimen? Final histopathology is the “Gold Standard” but would you agree it is an “imperfect” Gold Standard? Based on an average size specimen of 4.2 cm, it would take days to analyze the whole thing. Total sequential embedding results in 0.2% of the total specimen analyzed under the microscope. Multiple factors can impact final results: orientation, ink seeping, tissue sampling. Pancake phenomenon. I read a pathology paper published out of MSK where the authors acknowledged variation over when to “call” something positive. Between 5 different pathologists, they agreed only 30% of the time. (MSK Paper: ADH vs. DCIS?) Orientation can be lost approx.. 30% of the time. The only comparison of MarginProbe to a true gold standard is the Pappo study.  Point by point pathologic comparison showing sensitivity ave. to be 70% up to 100% with larger feature size.  Results were found to be the same across IDC, ILC and DCIS with detection maintained down to a single malignant DCIS duct. Up to 20% of “false positives” are found to contain malignancy in shaved tissue. (Articles: Thill, Schnabel, Blohmer, Coble, and Kupstas, Pellicane (poster) False Negatives: “MarginProbe missed a margin last week and that lady needs a re-excision” I understand how frustrating that can be. Let’s take a look at that pathology report. Oh-I see here that the medial margin was focally positive. Remember from our training that MarginProbe is looking for microscopic disease, down to 1mm or a single DCIS duct. Oh-I see that MP called the later margin positive and the anterior margin negative. But Pathology called the anterior margin positive and the lateral negative. Typically when we see this, orientation could have been the issue. The next case we do, I’ll follow the specimen to pathology and talk with them to make sure they are using the border markings when they paint. Or…if it has happened on several occasions, ask if they would consider painting their own margins in the OR? Lastly, pay attention to how many readings they are doing on each margin, focusing on full coverage. Sometimes if the tissue is very fatty and difficult to handle, it is possible they don’t take enough measurements because they keep getting the “honking” sound when not on the tissue properly. Mention this so they are more cognizant of the number of readings they are doing and the amount of surface areas they are covering. (Articles: Sebastian, Kuptas, Wachsmuth Poster, Data Reviews, Tozbikian, Molina) Dense Breasts “MarginProbe is not specific enough in dense breasts.” Ot “MarginProbe has too many false positives in dense breasts” Yes, dense breasts present a challenge with all screening modalities. The challenging part is that breast density, as an independent risk factor, increases holds a 4-6x greater risk of cancer. There is published data that show that re-excision rates actually increase based on breast density, as high as 42% in extremely dense patients. Based on the published data, extremely dense patients compromise approximately 10% of the population. How does that compare with your practice? Many other physicians have felt that MP wasn’t as effective in dense breast, but what they found was when they followed MP direction they had, on average, 3 overcalled margins but more true positives, which resulted in more of a reduction in re-excisions and overall, less tissue removed. In the fatty breast, overall tissue volume removed is 13.8 cc. In the dense breast, the overall tissue removed totaled 11cc. Many of our users believe that this is due to the way the tissue cuts. They feel they have more control over the shave. “Then I’ll just do FCS on everyone.” Yes, I can see why you’d think that was a good approach. We’ve actually had several surgeons compare their historical data to their data when using MarginProbe. What they found was. By using MP, they took 32% LESS tissue AND reduced their re-excision rate by 56%. If the 2-3 “false positves” bothered you with MP, wouldn’t the “six” false positives that would occur for every case, bother you even more? (Reference Aricles: Schnable & Allweis, Bani, Police poster, Walsh, Gooch, Weintritt mid-way data review)  Clinical Need “My re-excision rate is very low, I don’t need this. The new guidelines helped.” That’s great that your re-excision is so low so I can see understand why you would feel you don’t need MP. Do you track your re-excision rate as part of a quality measure for the Breast Center? I’d be curious to see if you have teased out those cases by cancer type? What we’ve found is that in the DCIS or IDC + DCIS or ILC, most surgeons end up seeing higher re- excisions (as high as 40%) How often do you see DCIS component in a case that was diagnosed as IDC in the biopsy pre-op imaging? We find quite often that we are able to find DCIS on cases that otherwise would have been undetected until final pathology. (You can reference the data collection process) Marketscan data (Chavez-MacGregor) released last year of 38,000 patients post new guidelines actually discuss a re-excision rate across the board as varying from 10-50% which we believe substantiates the need for an improvement in SOC, and as well a solution for DCIS which doesn’t seem to have been impacted with the new guidelines. The overall reduction was 15% and actual re-excision rate was 21.6%. What we see in the literature, MP Has been shown to reduce re-excision rates anywhere from 51-79% from the surgeon’s starting point ad was beneficial as an adjunct to all of the procedures and techniques you describe above. Interestingly, while the ASBrS believes in reducing the re-excision rate to below 10%, a recent analysis of claims data reports that 78.6% of physicians have a re-excision rate exceeding 10%. In a paper that compared the association of breast density and re-excision, DCIS was seen in 80.7% of the cases as a component to the invasive disease. (Reference Articles: Pappo, Thill, Meta-Analysis post “No Tumor on Ink” Guideline, Chavez-MacGregor, Kaczmarski, Walsh)  ® Sterile Disposable Probe Instructions for Use ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  1 COPYRIGHT © 2020 Dilon Medical Technologies Ltd. All rights reserved worldwide. This work and all rights herein are owned exclusively by Dilon Medical Technologies Ltd., its subsidiaries and its other affiliated corporations. No parts of this manual, in whole or in part, may be reproduced, performed, published, displayed, broadcast, translated, or transmitted to any electronic medium or machine readable form, distributed, sold or otherwise used or relied upon without the express prior written permission of Dilon Medical Technologies Ltd. Reproduction or reverse engineering of copyrighted software is prohibited. PATENTS This product is protected by the following US Patents: 7,899,515; 7,904,145; 8,019,411; 8,147,423; 8,195,282; 8,319,502. This product is protected by the following Chinese Patent: ZL200680019026.4. Other patent applications are pending in the USA, China, Japan and Europe, including: EP1890596; EP1919273; EP2118801; EP2129281; EP2304456. TRADEMARKS MARGINPROBE is a registered trademark of Dilon Medical Technologies Ltd. All product names and any registered and unregistered trademarks mentioned in this Instruction for Use that refer to goods or services offered by Dilon Medical Technologies Ltd., its subsidiaries and other affiliated companies are owned by Dilon Medical Technologies Ltd. All third-party product names and any registered or unregistered trademarks mentioned in this Instruction for Use that refer to goods or services offered by parties other than Dilon Medical Technologies Ltd. remain the property of their respective owners. IFU Part Number: PB0501051 Revision Level: E Revision Date: June 2020 ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  2 Indications for Use The MARGINPROBE® System is an adjunctive diagnostic tool for identification of cancerous tissue at the margins (≤ 1mm) of the main ex-vivo lumpectomy specimen following primary excision and is indicated for intraoperative use, in conjunction with standard methods (such as intraoperative imaging and palpation) in patients undergoing breast lumpectomy surgery for previously diagnosed breast cancer. Device Description The MARGINPROBE® System is a medical device comprised of a probe and a console that are packaged and sold separately. - The console has a user interface system with display, audio components and operation buttons. - The probe is a detachable, sterile, single-use, single-patient component with a 3-year shelf life. It is connected to the console by two RF cables and a vacuum tube, via a single connector. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  3 The MARGINPROBE® System is used in patients undergoing breast surgery as an adjunct to standard methods of margin assessment. It is used on excised tissue immediately following excision (i.e., within 20 minutes) to measure the dielectric properties of the tissue and to characterize it as malignant (positive) or normal (negative). Expected duration of intraoperative device use is 5 minutes. The MARGINPROBE® System is designed based on the principles of dielectric spectroscopy to characterize Figure 1. MarginProbe® System tissue. It applies an electric field to the tissue through a sensor mounted at the tip of the probe and analyzes the reflection over a wide range of RF frequencies. The RF energy is confined to the vicinity of the probe tip. The energy level per measurement is less than 0.2 mJ with a power lower than 0.3 mW. The maximum field voltage is 1V p-p. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  4 The probe has a footprint of 1.6 cm in diameter and effective measurement area of 7 mm. A light vacuum (0.4-0.6 ATM) secures the probe to the tissue during measurement. The device uses a classification algorithm that was created using breast cancer tissue samples. The sensor creates an electromagnetic field which exponentially decays in the tissue. The field decays by approximately 60% through the first 1.5mm of tissue and by approximately 80% through the first 3mm of tissue. The algorithm and clinical studies for the MARGINPROBE® device assessed lumpectomy tissue readings at the surface margins ≤ 1 mm in depth. The MARGINPROBE® System Probe should be used to sample the entire surface of the specimen, taking approximately 5-8 measurements per margin surface, and up to 12 points per face for larger specimens. Measurements should be performed at both evenly spaced intervals and suspicious sites. Readings are displayed on the MARGINPROBE® System Console as either positive or negative. If any one of the device readings is positive, the margin should be considered positive, and an appropriate surgical action should be taken. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  5 Contraindications The MARGINPROBE® System should not be used: To replace standard tissue histopathology assessment On ex-vivo lumpectomy specimens that have been exposed to saline, ultrasound gel or local anesthetic solutions On in-vivo tissue (i.e. it should not be used within the lumpectomy cavity) On tissues other than breast tissue (i.e. it should not be used on Sentinel Lymph Nodes) Closer than 1.5 mm to a fine needle localization guidewire Warnings The MARGINPROBE® should be used on tissue specimens within 20 minutes of excision. The MARGINPROBE® should not be used in patients who undergo full cavity excision following removal of the main lumpectomy specimen during the initial lumpectomy procedure. The MARGINPROBE® has not been studied in patients with: - Multicentric disease (histologically diagnosed cancer in two different quadrants of the breast), unless resected in a single specimen - Bilateral disease (diagnosed cancer in both breasts) - Neoadjuvant systemic therapy - Previous radiation in the operated breast - Prior surgery at the same site in breast - Implants in the operated breast - Pregnancy - Lactation - Cryo-assisted localization ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  6 Precautions The main ex-vivo lumpectomy specimen is defined as the initially excised lumpectomy specimen, without any of the lumpectomy cavity shavings that may have been subsequently taken during the procedure. The device has not been studied for use on tissue shavings excised from the lumpectomy cavity. The MARGINPROBE® System should be used in addition to standard intraoperative methods of assessing margin status. Moving the probe before suction release may potentially damage and affect tissue histopathology. The MARGINPROBE® Probe should only be used with the MARGINPROBE® Console. The MARGINPROBE® Probe is designed for single patient, single- use only and must be properly discarded after use. The MARGINPROBE® Probe is supplied sterile. If the sterile pack is torn or has been opened, do not use the probe. Do not use a MARGINPROBE® Probe that has passed its expiration date. Potential Adverse Effects of the Device on Health Below is a list of the potential adverse effects (e.g., complications) associated with the use of the device. Extension of procedure time Errors in device reading Unnecessary removal of healthy tissue with a potential negative impact on cosmetic results or cosmetic appearance Infection Local tissue damage Bleeding For the specific adverse events that occurred in the clinical studies, please see the next section (Clinical Data) below. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  7 Clinical Data [MarginProbe Pivotal Study] A clinical pivotal study was performed to establish a reasonable assurance of safety and effectiveness of the MarginProbe System. The MarginProbe System is an adjunctive diagnostic tool for identification of cancerous tissue at the margins (≤ 1mm) of the ex- vivo lumpectomy specimen following primary excision and is indicated for intraoperative use, in conjunction with standard methods (such as intraoperative imaging and palpation) in patients undergoing breast lumpectomy surgery for previously diagnosed breast cancer in the US. The pivotal study was performed under IDE # G070182. Data from this clinical study were the basis for the PMA approval decision. A summary of the clinical study is presented below. A. Study Design Patients were treated between September 2008 and March 2010. The MarginProbe System pivotal study was a prospective, multicenter, randomized (1:1), controlled, double-arm study. Breast cancer patients were randomized to either receive standard of care (SOC) lumpectomy or Standard of Care lumpectomy with adjunctive MarginProbe device use (SOC + Device). Key Aspects of the protocol are as follows: 1. Patient Study Inclusion and Exclusion Criteria Enrollment in the pivotal study was limited to patients who met the following inclusion criteria: Women histologically diagnosed with carcinoma of the breast Women with non-palpable malignant lesions, requiring image guided localization. Undergoing lumpectomy (partial mastectomy) procedure. Age 18 years or more Signed informed consent form ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  8 Patients were not permitted to enroll in the pivotal study if they met any of the following exclusion criteria: Multicentric disease (histologically diagnosed cancer in two different quadrants of the breast) Bilateral disease (diagnosed cancer in both breasts) Neoadjuvant systemic therapy Previous radiation in the operated breast Prior surgical procedure in the same breast Implants in the operated breast Pregnancy Lactation 2. Patient Treatment Patients were first enrolled and taken to the operating room for resection of the main lumpectomy specimen. The main lumpectomy specimen and lumpectomy cavity palpation and related re-excisions were performed before patient randomization. For all main specimens, the center of each of the 6 margins was suture marked. Patient were then randomized to either the SOC or SOC+Device arm intraoperatively, immediately after the main lumpectomy specimen was excised, oriented, center marked, palpated, and additional palpation based re-excision performed. For patients randomized to the SOC+Device arm the surgeon: Applied the MarginProbe device to each of the 6 faces of the excised main lumpectomy specimen—sampling 5 – 8 points (and up to 12 points for larger specimens). The points sampled were at both evenly spaced and suspicious sites. Was required to react to Device feedback. A single positive reading on any margin classified that margin as positive and required the surgeon to remove additional tissue from that margin. Documented the reasons why additional margins were not re-exicised despite a positive MarginProbe device reading. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  9 For the purposes of CSR primary endpoint calculations, lumpectomy cavity shavings that were not possible due to physical limitations (proximity to the skin or pectoralis fascia) the margin was considered “addressed” Was instructed not to use the MarginProbe device on shavings from the lumpectomy cavity shavings (even if a shaving was taken prior to randomization) Was instructed not to use the MarginProbe device within the in-vivo lumpectomy cavity. Was instructed not the use the MarginProbe device on ex- vivo lumpectomy tissue that had been exposed to saline or ultrasound gel. It was however acceptable to use the MarginProbe device on ex-vivo lumpectomy tissue exposed to sterile water. Was instructed not to use the MarginProbe device in the 1.5 mm region of tissue surrounding a fine needle localization guidewire. For both SOC and SOC+Device arm patients, lumpectomy specimens were imaged by ultrasound or radiography after randomization and device use. Additional lumpectomy cavity re-excisions were taken as deemed appropriate based on specimen imaging results. Figure 2 provides a diagrammatic representation of the study design. Note that the study design allows for an additional option to perform lumpectomy cavity shavings in the SOC+Device arm (option for shaving at 3 time points) versus the SOC arm (option for shaving at 2 time points). ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  10 Figure 2 - Pivotal Study Design The MarginProbe device was not used during lumpectomy reoperations. The study consisted of two phases – a training phase and a randomization phase. Each surgeon had to complete the training phase before being able to randomize patients. Surgeons who had attended 2 or more device procedures (training or randomized) were certified in device use. 3. Pathology Protocol Pathological assessment was standardized and identical for both study arms. Pathologists were blinded to randomization. A positive margin was to be defined in this study as a margin microscopically measured and reported in the histopathology report to have cancer within 1 mm or less of the inked surface. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  11 Each investigational site performed the histopathology assessment using a Standard Operating Procedure. Re-cut slides from the first 4 patients at each investigational site (Training, SOC, or SOC+Device) were to be sent to a core-lab and were to be used to review the accuracy and reporting capabilities of the investigational site pathology. Dimensions (L, W, D) of all excised tissues were recorded. Tissue volume was determined by use of the ellipsoid formula: V= (4/3)*π*L*W*D 4. Duration of Patient Follow-up Patients were followed until the end of the lumpectomy procedure. Data were collected regarding all ipsilateral breast surgical procedures and their respective permanent histopathology data. Data were to be collected up until the earlier of the following events: conversion to mastectomy, initiation of chemotherapy or two months after the surgery date. 5. Study Endpoints The prespecified study endpoints are as follows: Safety evaluation consisted of assessment of all adverse events and serious adverse events, which were summarized using descriptive statistics. The primary effectiveness endpoint (CSR) is measured as all pathologically positive margins on the main specimen being intraoperatively re-excised or “addressed”. A re-excised or “addressed” margin does not mean that the final true outermost margin is pathologically negative for cancer. A positive margin is defined as a margin microscopically measured and reported in the histology report to have cancer within 1 mm or less of the inked margin. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  12 The main specimen is defined as the lumpectomy specimen removed prior to patient randomization. The main lumpectomy specimen does not include additional shavings even if the cavity shaving was performed prior to patient randomization. If a margin has been indicated as positive by the device and documented to not have been re-excised as required by protocol, due to resection already undermining the skin or reaching the pectoralis fascia, this margin will be counted as “detected” and “addressed” for the purpose of CSR endpoint calculation although it was not “re-excised”. An illustration of how CSR is determined is provided in Figure 3. Figure 3 - Illustration of CSR Primary Endpoint ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  13 Figure 4 below illustrates how the CSR assessment includes both clinically relevant scenario which is the conversion of a specimen which has a pathologically positive for cancer margin to a specimen with negative for cancer margins and the clinically irrelevant scenario in which the additional shaving resulted in the true outermost margin of the specimen remaining pathologically positive for cancer. Figure 4 - CSR and Clinical Relevance While CSR is a focused assessment that is limited to what is within the control of the MarginProbe device, there are limitations to the CSR primary effectiveness endpoint. Some of these limitations are present because the reason and timing for taking additional shavings of the lumpectomy cavity were not documented—that is, whether a shaving was taken because of clinical suspicion, imaging, other assessment, versus a positive MarginProbe device reading and whether the shaving was taken before randomization or after specimen imaging. While the device ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  14 readings for each margin and the margins shaved were documented, the timing of each shaving and the reason prompting the shaving was not collected. Table 1 summarizes the strengths and limitations of the CSR primary effectiveness endpoint for the pivotal study. Table 1 - Strengths and limitations of the primary effectiveness endpoint, CSR Strengths Limitations A focused assessment The study design allows for an additional limited to what is within option to perform cavity shavings in the the control of the SOC+Device arm versus the SOC arm. The MarginProbe device i.e. additional option in the SOC+Device arm causing additional cavity may be responsible for an increase in CSR in shavings. the SOC+Device arm. A by specimen assessment The incremental contribution of the which does not give partial MarginProbe device to a higher CSR credit to intraoperative re- cannot be determined because the exision of some positive reason for taking a cavity shaving - i.e. margins on the main SOC (clinical suspicion, or imaging) specimen but not all versus a positive MarginProbe reading positive margins on the - was not documented. main specimen. Questionable clinical relevance. CSR considers whether a shaving was taken or not taken at positive margins on a lumpectomy specimen. CSR does not consider whether the shaving taken converted the initially positive for cancer margin to a negative for cancer final margin. CSR does not penalize false positive MarginProbe readings in the positive main specimen cohort. False positive MarginProbe readings in the positive ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  15 main specimen cohort cause the resection of healthy tissue. CSR does not consider false positive MarginProbe readings in the negative main specimen cohort. False positive MarginProbe readings in the negative main specimen cohort cause the resection of healthy tissue. Secondary effectiveness endpoints are summarized in Table 2 below. Table 2 - Secondary Effectiveness Endpoints Endpoint Definition Incomplete Surgical Proportion of patients with at least Re-excision 1 positive margin not resected/addressed. Differs from primary effectiveness endpoint, CSR, since Yes/No definitions are opposite. Differs from the CSR endpoint since it is calculated from the AVS dataset rather than the PSS dataset. Full Detection Rate of patients with all positive margins on main specimen detected by device Re-excision Rate of repeated ipsilateral breast Procedure Rate surgical procedures (including mastectomies) Positive Margin Rate of patients with at least 1 Presence positive margin remaining after lumpectomy TTV excised in the Average volume of total amount of primary tissue excised in lumpectomy lumpectomy procedure (cm3) ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  16 6. Pre-Specified Analysis Plan For the primary efficacy analysis, a sample size of 116 valid primary effectiveness patients per arm was determined to provide at least 90% power to demonstrate superiority of SOC+Device over SOC. The analysis populations are defined in Table 3. Table 3 - Analysis Populations Analysis Definition Population All Valid The AVS subjects included all randomized Subjects patients with valid histology data (and valid (AVS) MarginProbe System data in Device arm) Positive The PSS subject is a subset of the AVS Analysis Specimen Set of subjects with at least 1 histologically Subjects positive main specimen margin at depth ≤1 mm (PSS) Negative The NSS subject is a subset of the AVS Analysis Specimen Set of subjects with no histologically positive Subjects main specimen margin at depth ≤1 mm. (NSS) Safety was assessed using the AVS population. The primary effective endpoint was based on PSS population, and the secondary effectiveness endpoints were based on AVS, PSS or NSS populations as shown in Tables 4 and 5. Table 4 - The Primary Effectiveness Endpoints Population Endpoint Analysis Scoring Population PSS Complete Surgical Re-excision CSR analysis set (CSR) was scored dichotomously as follows: No: At least one positive margin on the main specimen not re- excised/addressed ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  17 intraoperatively. Yes: All positive margins on the main specimen re- excised/addressed intraoperatively Table 5 - The Secondary Effectiveness Populations Endpoint Analysis Scoring Population Incomplete AVS analysis Incomplete Surgical Re-excision Surgical set. (“re-excision is used to mean Re-excision “resection) was scored The groups dichotomously: were compared using 2-sided Yes: If at least 1 positive margin Fisher’s Exact with d ≤ 1 mm on the main Test. specimen was not resected/addressed intraoperatively. No: Otherwise This endpoint differed from the primary effectiveness endpoint, Complete Surgical Resection since the Yes/No definitions were opposite. Full PSS analysis set Scored dichotomously for Detection SOC+Device arm patients only: A 2-sided exact binomial 95% Yes: If all positive margins on CI for the the main specimen with d ≤ 1 proportion of mm were detected by the device "Yes”. (in Device arm) No: Otherwise ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  18 Endpoint Analysis Scoring Population Re-excision AVS analysis Number of repeated ipsilateral Procedure set breast surgical procedures Rate (including mastectomies) for Compared the each patient. This endpoint was groups using a counted as an integer per patient; Poisson the count was increased by 1 regression with each subsequent surgery. model. Positive AVS analysis Scored dichotomously. Margin set Presence Yes: If there was at least 1 Compared the positive margin with d ≤ 1 groups using a mm after the first Poisson lumpectomy regression model. No: Otherwise TTV excised NSS analysis Total amount of tissue in the primary set excised during lumpectomy lumpectomy for each procedure Compared the patient. (cm3) groups using a 2-sided Wilcoxon Rank-Sum Test. The margin-level and patient level (ignoring location) sensitivity and specificity are reported for diagnostic performance of the MarginProbe device. These were not pre-specified in terms of an acceptable minimal sensitivity and specificity. The results here are based on the observed performance in the clinical pivotal study. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  19 B. Subject Accountability A total of 664 patients who were eligible for study enrollment underwent surgery and were allocated to either the roll-in group or randomization (enrollment allocation). Sixty-eight women were operated on in the roll-in phase and 596 were randomized equally to the Control (SOC arm) and Device treatment (Device +SOC arm) groups. All 664 women completed the study. Subject accountability is displayed below in Table 6. Table 6 - Patient Accountability, Pivotal Study Disposition Total n (%) Eligible for Participation 721 Did Not Enter Study 57 (7.9) Failed eligibility 25 (3.5) Withdrew consent 6 (0.8) Other 26 (3.5) Eligible for Allocation 664 (92.1) Allocated to Enrollment 664 (100) Roll-in 68 (10.2) Randomized to Treatment 596 (89.8) Device 298 (44.9) Control 298 (44.9) Completed Study 664 (100) Did Not Complete 0 (0) All 664 women were included in the Safety analysis set. The AVS analysis set includes 596 randomized (298 Device and 298 Control) patients and differs from safety analysis set in 64 roll-in women, as shown in Table 7. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  20 Table 7 - Data Sets Analyzed: Number of Patients Analysis Patients Treatment Group Set Included Device n (%) Control n (%) Roll-In n (%) Total n (%) Safety All patients for 298 (100.0) 298 (100.0) 68 (100.0) 664 (100.0) Set whom surgical procedure was initiated Effectiveness Sets AVS All Randomized 298 (100.0) 298 (100.0) NA 596 (100.0) Patients PSS Positive Specimen 163 (54.7) 147 (49.3) NA 310 (52.0) Patients NSS Negative 135 (45.3) 151 (50.7) NA 286 (48.0) Specimen Patients All randomized patients completed the study protocol. There was no loss to follow-up in the study. There was no missing data related to the CSR endpoint; 38/1788 (2%) of margins were not measured by the device. C. Demographics and Baseline Characteristics Demographic characteristics were similar for the Device and Control groups. Overall, the groups appeared to be comparable, as shown in Table 8 and 9. Table 8 - Demographics by Treatment Group Treatment Group Roll-In Device Control Parameter N=68 N=298 N=298 Ethnic Origin n (%) Whitea 59 (86.8) 250 (83.9) 260 (87.2) African-American or Black 5 (7.4) 22 (7.4) 17 (5.7) Asian 2 (2.9) 12 (4.0) 10 (3.4) Native Hawaiian or Other Pacific Islander 0 (0) 3 (1.0) 1 (0.3) Other 2 (2.9) 11 (3.7) 10 (3.4) a Includes Hispanics. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  21 Table 9 - Baseline Characteristics by Treatment Group Treatment Group Roll-In Device Control Parameter N=68 N=298 N=298 Age (yrs) Mean (SD) 63.6 (11.1) 60.3 (11.4) 60.2 (11.1) BMI (mean) 28.0 27.9 28.6 Bra Cup Size n (%) AA 0 (0.0) 2 (0.7) 4 (1.3) A 6 (8.8) 16 (5.4) 16 (5.4) B 21 (30.9) 101 (33.9) 73 (24.5) C 24 (35.3) 99 (33.2) 93 (31.2) D 12 (17.6) 62 (20.8) 92 (30.9) E 1 (1.5) 2 (0.7) 5 (1.7) F 1 (1.5) 1 (0.3) 1 (0.3) >F 1 (1.5) 1 (0.3) 2 (0.7) Unknown 2 (2.9) 14 (4.7) 12 (4.0) Table 10 presents the number of patients with a diagnosis, requiring that certain categories be combined. For patients with invasive types of carcinoma the mixed invasive category was used, and for patients with more than 1 diagnosis who did not have more than one type of invasive carcinoma, the mixed category was used. The treatment groups appear to be similar with respect to diagnosis. Table 10 - Patient Diagnosis by Treatment Group (Per-diagnosis Analysis) Treatment Group Roll-In Device Control Phase All N (%) N (%) N (%) N (%) Patient Diagnosis Patients Patients Patients Patients Invasive Ductal Carcinoma 24 (8.1) 22 (7.4) 7 (10.3) 53 (8.0) Invasive Lobular Carcinoma 26 (8.7) 13 (4.4) 2 (2.9) 41 (6.2) Mixed Invasivea 8 (2.7) 5 (1.7) 1 (1.5) 14 (2.1) Ductal Carcinoma in Situ 83 (27.9) 78 (26.2) 19 (27.9) 180 (27.1) Tubular Carcinoma 1 (0.3) 0 (0.0) 0 (0.0) 1 (0.2) Mucinous Carcinoma 1 (0.3) 1 (0.3) 0 (0.0) 2 (0.3) b Mixed 155 (52.0) 179 (60.1) 39 (57.4) 373 (56.2) Total 298 (100.0) 298 (100.0) 68 (100.0) 664 (100.0) a Mixed invasive=Invasive Ductal Carcinoma+Invasive Lobular Carcinoma. b Mixed=more than 1 diagnosis and not only invasive carcinoma. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  22 Tumor stage results are presented in Table 11 below. The majority of patients were diagnosed with stage II breast cancer and below. Table 11 - Tumor Stage 0 I II III IV Unknown Total Treatment Group N % N % N % N % N % N % N % Device 81 27.2 155 52.0 51 17.1 4 1.3 1 0.3 6 2.0 298 100.0 Control 84 28.2 161 54.0 44 14.8 6 2.0 0 0 3 1.0 298 100.0 Roll-In Phase 21 30.9 34 50.0 12 17.6 1 1.5 0 0 0 0 68 100.0 All 186 28.0 350 52.7 107 16.1 11 1.7 1 0.2 9 1.4 664 100.0 Receptor status is presented in Table 12. There were 84 subjects in device and control arms, and 19 in the roll-in subjects, for which HER2 status was not preformed. Table 12 - Receptor Status Receptor Roll-In Device Control Status N=68 N=298 N=298 ER+ 60/68 (88.2) 251 (84.2) 258(86.6) PR+ 52/68 (76.4) 223 (74.8) 217 (72.8) HER2+ 3/49 (6%) 20/214 (9%) 33/214 (15%) HER2- 42/49 (85%) 175/214 (82%) 163/214 (76%) D. Surgical Procedure The mean duration of anesthesia time (hours: minutes) was 2:03 for the Device group, 1:52 for the Control group and 2:11 for the Roll-in group. This time includes surgical procedures, resections, completion of the protocol procedures, and device use. The mean duration of device use was 5 minutes for the Device group and 6 minutes for the Roll-in group. Table 13 presents the number and percent of patients with a palpable tumor excised during lumpectomy. While all patients had non- palpable lesions at screening (inclusion criteria), the lesion may or may not have been palpable in the ex-vivo lumpectomy specimen. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  23 There were no apparent differences between treatment groups with respect to palpable tumors during excision. Table 13 - Frequency Distribution of Palpable Tumor during Lumpectomy by Treatment Group Various intraoperative evaluations were used at surgeon discretion in both the SOC and SOC+Device arms and included radiological exam, ultrasound, ultrasonic guidance, touch cytology, gross assessment, and frozen section. The reason for performing a lumpectomy cavity shaving—that is, whether a shaving was prompted by gross visualization/palpation, positive MarginProbe device readings, imaging, touch prep cytology or frozen section analysis--was not documented. The methods of excision used during lumpectomy included the following: electrocautery, sharp excision, and scissors. Table 14 describes number of patients undergoing SLNB with dye or radioisotope or both. Table 14 - Number of Patients undergoing SLNB with Dye or Radioisotope or Both Roll-In Device Control N=68 N=298 N=298 SLNB performed 59 (72%) 223 (75%) 225 (75) ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  24 E. Pathology Table 15 presents weight and volume of the main specimen. There were no apparent differences between treatment groups with respect to weight and volume of the main specimen. The mean size (diameter) of the main specimen was 4.85 cm for the Device group, 4.89 cm for the Control group, and 4.7 cm for the Roll-in group. Table 15 - Descriptive Statistics of Specimen Weight and Volume by Treatment Group Overall mean tumor size was similar for the groups (MarginProbe=1.7 cm3, Control=1.6 cm3). The tumor type (as assessed by post-operative histopathology) by treatment group are presented in Table 16. The treatment groups appear to be similar with respect to tumor type. The number of positive margins on the main specimen, by treatment group, also appears to be similar. Table 16 - Frequency Distribution for Tumor Type by Treatment Group Treatment Group Tumor Type Device Control Roll-In Phase All N Specimens (%) N Specimens (%) N Specimens (%) N Specimens (%) Invasive ductal 158 (53.0) 179 (60.1) 40 (58.8) 377 (56.8) carcinoma Invasive lobular 46 (15.4) 26 (8.7) 9 (13.2) 81 (12.2) carcinoma Ductal carcinoma 207 (69.5) 229 (76.8) 46 (67.6) 482 (72.6) in-situ Tubular 5 (1.7) 6 (2.0) 2 (2.9) 13 (2.0) Carcinoma ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  25 Mucinous 10 (3.4) 3 (1.0) 2 (2.9) 15 (2.3) Carcinoma Medullary 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Carcinoma Papillary 0 (0.0) 2 (0.7) 1 (1.5) 3 (0.5) Carcinoma Non malignant 19 (6.4) 19 (6.4) 5 (7.4) 43 (6.5) (NM) Other 5 (1.7) 7 (2.3) 0 (0.0) 12 (1.8) Total Patients 298 (100.0) 298 (100.0) 68 (100.0) 664 (100.0) The average weight and volume of resected margins by treatment group during the lumpectomy is presented in Table 17. The treatment groups appear to be similar with respect to weight and volume of resected margins. Table 17 - Descriptive Statistics of Resected Margins Weight and Volume by Treatment Group F. Study Results 1. Safety Results 14 adverse events (AEs) were reported, all being categorized as serious adverse events (SAEs) per study protocol definition. One SAE was possibly related to the study device, a wound infection requiring hospitalization and treatment with antibiotics. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  Treatment Group Device Control Roll-In Phase Any N=298 N=298 N=68 N=664 System Organ Class/Preferred N (%) N (%) N (%) N (%) Term N SAEs Patients N SAEs Patients N SAEs Patients N SAEs Patients Any Any 6 6 (2) 5 5 (2) 3 3 (4) 14 14 (2) Any 2 2 (1) 1 1 (0) 2 2 (3) 5 5 (1) Acute tonsillitis 1 1 (0) 0 0 (0) 0 0 (0) 1 1 (0) Breast abscess 0 0 (0) 1 1 (0) 0 0 (0) 1 1 (0) Infections and Cellulitis 0 0 (0) 0 0 (0) 1 1 (1) 1 1 (0) infestations Postoperative wound infection 1 1 (0) 0 0 (0) 0 0 (0) 1 1 (0) Urinary tract infection 0 0 (0) 0 0 (0) 1 1 (1) 1 1 (0) Any 2 2 (1) 3 3 (1) 0 0 (0) 5 5 (1) Fractured sacrum 1 1 (0) 0 0 (0) 0 0 (0) 1 1 (0) Injury, poisoning and 26 Post procedural procedural haemorrhage 0 0 (0) 2 2 (1) 0 0 (0) 2 2 (0) complications Procedural dizziness 1 1 (0) 0 0 (0) 0 0 (0) 1 1 (0) Procedural pain 0 0 (0) 1 1 (0) 0 0 (0) 1 1 (0) Neoplasms benign, Any 1 1 (0) 0 0 (0) 0 0 (0) 1 1 (0) malignant and unspecified (incl cysts and polyps) Uterine leiomyoma 1 1 (0) 0 0 (0) 0 0 (0) 1 1 (0) Organ Class, Preferred Term, and Treatment Group Reproductive system Any 0 0 (0) 1 1 (0) 0 0 (0) 1 1 (0) and breast disorders Breast haematoma 0 0 (0) 1 1 (0) 0 0 (0) 1 1 (0) Any 1 1 (0) 0 0 (0) 1 1 (1) 2 2 (0) Caution: Federal law restricts this device to sale by or on the order of a physician. Vascular disorders Hypertension 0 0 (0) 0 0 (0) 1 1 (1) 1 1 (0) Hypertensive crisis 1 1 (0) 0 0 (0) 0 0 (0) 1 1 (0) Table 18 - Frequency of Serious (All) Adverse Events by System ____________________________________________________________________________________ PB0501051  27 Adverse events associated with device malfunction or incorrect device readings causing incorrect surgeon action is both a safety and an effectiveness issue. Incorrect surgeon action is therefore further discussed in the Effectiveness Results section below. While an approximately 5 minute prolongation of the operative procedure associated with device use, this prolongation cannot be associated with specific patient adverse events. In addition, while damage to the tissue exposed to the MarginProbe device is a potential problem, an assessment for tissue damage was not considered to be feasible in the pivotal study. From the available data this issue has not been reported. 2. Effectiveness Results Primary Effectiveness Endpoint: There were a total of 163 patients in the SOC+Device arm and a total of 147 patients in the SOC arm who were in the PSS dataset (i.e. with at least one positive margin by histology on the main specimen). The CSR primary effectiveness endpoint results are provided in Table 19. The device failed to give a reading on 38 (2%) margins out of 1788 margins measured from 298 subjects. This did not impact the primary endpoint. Table 19 - The CSR Primary Effectiveness Endpoint Results Primary Dataset SOC + SOC Difference Endpoint Device (95% CI) CSR PSS 71.8% 22.4% 49.3% p< (117/163) (33/147) (39.0%,58.7%) 0.0001 ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  28 Table 20 - Secondary Effectiveness Endpoint Results Secondary Dataset SOC + SOC p-value or Endpoints Device CI Incomplete AVS 15.4% 38.3% p < 0.0001* Surgical (46/298) (114/298) Re-excision Full Detection PSS 62.6% NA 95% CI: (102/163) 54.7% – 70%* Re-excision AVS 20.8% 25.8% p = 0.3177* Procedure Rate (82/298) (94/298) Positive AVS 30.9% 41.6% p = 0.0082* Margin (92/298) (124/298) Presence TTV excised in NSS 92.7 cm3 69.9 cm3 p = 0.0031* the primary lumpectomy procedure (cm3) * Unadjusted analysis Of the endpoints listed, the clinically relevant endpoint of re-excision procedure rate showed a 5 percentage point reduction in the SOC+Device arm versus SOC arm. The reoperation procedure rate is further described in Table 21. Note that fewer patients in the SOC+Device arm required a second operation (71 patients in the SOC+Device arm versus 85 patients in the SOC arm). Recall that the MarginProbe device was only used during the initial lumpectomy operation and not during reoperations. More patients in the SOC+Device arm versus the SOC were converted to mastectomy. There are numerous reasons for conversion to mastectomy and therefore this finding cannot be directly attributable to device use. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  29 Table 21 - Reoperation Procedure Rate Re-excision (including conversion to mastectomy) Additional p- Lumpectomy Total Resections Value Procedure # 1 2 3 4 71 SOC+Device 298 62 7 2 (23.8%) 0.3177 85 SOC 298 77 7 1 (28.5%) Conversion to mastectomy in device arm = 18/298 p = 0.46 Conversion to mastectomy in control arm = 13/298 The following additional analyses, Table 22 and Table 23, provide information regarding diagnostic performance of the device per margin and per patient (ignoring location). Table 22 - Diagnostic Performance (per-margin) Sensitivity(%) Specificity(%) PPV†(%) NPV†(%) (95% CI)‡ (95% CI) ‡ (95% CI) ‡ (95% CI) ‡ SOC+Device 73.8 45.1 21.6 89.4 (68.1,79.4) (41.8,48.3) (20.1,23.1) (87.2,91.4) SOC 33.9 83.4 29.5 86.0 (27.5,40.5) (81.1,85.7) (25.1,34.3) (84.8,87.2) (SOC+Device)-SOC 39.9 -38.3 -7.9 3.4 (31.4,48.1) (-42.4, -34.5) (-12.8,-3.4) (1.0,5.7) Device only†† 75.2 46.4 22.3 90.1 (69.3,80.5) (42.6,49.9) (20.7,23.8) (88.0,92.1) SOC 33.9 83.4 29.5 86.0 (27.5,40.5) (81.1,85.7) (25.1,34.3) (84.8,87.2) Device-SOC 41.3 -37.0 -7.2 4.1 (33.0,49.5) (-41.4, -33.0) (-12.1,-2.6) (1.8,6.4) ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  30 †PPV and NPV calculated using Bayes theorem on sensitivity and specificity, assuming a common prevalence across the two study arms of 17.0%. ‡95% Bootstrap percentile intervals. †† There were 38 margins with a missing device reading (6 pathology positive margins and 32 pathology negative margins) Table 23 - Diagnostic Performance per patient ignoring location Sensitivity(%) Specificity (%) PPV†(%) NPV†(%) 95% CI 95% CI 95%CI 95% CI SOC+Device 98.8 5.9 53.2 81.9 (95.6,99.9) (2.6,11.3) (52.1,54.4) (49.0,95.4) SOC 68.7 53.6 61.6 61.3 (60.1,76.1) (45.4,61.8) (56.7,66.3) (54.4,67.7) (SOC+Device)- 30.1 -47.7 -8.4 20.6 SOC (22.6,38.2) (-56.6, -38.3) (-13.6, -3.5)‡ (-9.2,42.0)‡ Device only 96.3 8.9 53.4 68.9 (92.2,98.6) (4.7,15.0) (51.9,54.9) (46.2,85.2) SOC 68.7 53.6 61.6 61.3 (60.1,76.1) (45.4,61.8) (56.7,66.3) (54.4,67.7) Device-SOC 27.6% -44.7% -8.2 7.6 (19.6,36.0) (-54.0, -34.9) (-13.5,-3.1)‡ (-16.6,27.9)‡ †PPV and NPV calculated using Bayes theorem assuming a common prevalence across the two study arms of 52%. ‡95% Bootstrap percentile intervals. The Figures 4 and 5 provide a more comprehensive assessment of what occurred in each arm of pivotal study. As shown in Figure 5, 298 SOC patients were enrolled. An average of 72 cm3 of tissue was excised during the initial lumpectomy. There were 147 patients with cancer positive main specimens and 151 cancer negative main specimens. Of the 147 cancer positive main specimens, 25 or 17% were converted to cancer negative final margins with cavity shavings. In the SOC arm, shavings were not taken in 46+81 or 127/298 subjects. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  31 Figure 5 - Pivotal Study Patient Flow Chart - SOC Arm As demonstrated in Figure 6, 298 patients were enrolled in the SOC+Device arm. An average of 88 cm3 of tissue was excised during the initial lumpectomy. There were 163 patients with cancer positive main specimens and 135 cancer negative main specimens. Of the 163 cancer positive main specimens, 79 or 49% were converted to cancer negative final margins with cavity shavings. In the SOC+Device arm, shavings were not taken in 2+8 or 10/298 subjects. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  32 Figure 6 - Pivotal Study Patient Flow Chart - SOC+Device Arm Summary of Supplemental Clinical Information A. Pivotal Study Additional Analyses While not powered to detect differences across subpopulations, there was a trend for outside of US patient populations to experience greater clinically relevant benefit than for the US population of patients enrolled as shown in Table 24. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  33 Table 24 - Pivotal Study Results across Subpopulations US Patients Israel Patients n = 566 n = 98 Endpoint SOC + Device SOC SOC + Device SOC 1º CSR 69.7% 22.4% 85.7% 22.7% 2º Incomplete 17.3% 38.8% 6.1% 35.4% Surgical Re-excision 2º Full Detection* 59.9% N/A 81% N/A 2º Re-excision 34.5% 48% 4.8% 22.7% Procedure Rate 2º Positive Margin 53.5% 82.4% 38.1% 86.4% Presence 2º Total Tissue 92.4 82.6 97.6 95.9 Volume Excised 3 (cm ) Diagnostic Device SOC + Device SOC SOC + Device SOC Performance Sensitivity (%) 73.4 87.8 95% CI† (66.8,79.6) (76.8,98.8) Specificity (%) 44.7% 53.9% 95% CI† (40.8,48.8) (46.0,62.0) *Full detection is for Device (not SOC+Device arm) †95% Bootstrap percentile intervals. B. Product Development Clinical Studies Product development clinical studies were conducted at various stages of the product development process, as summarized in Table 25. None of these studies were pre-approved by FDA. ____________________________________________________________________________________ Caution: Federal law restricts this device to sale by or on the order of a physician. PB0501051  34 Table 25 - Summary of Developmental Clinical Studies Study # Product Primary Study Name Principal Results Number Subjects Description Objective “Point-by- N=76 MarginProbe Obtain database Device use has no point” study System Probe & set and assess permanent effect on in pathology MarginProbe performance – tissue (macroscopic or - phase II System Type 1.0 phase II microscopic) 3/2006 – system console Device performance per- 6/2007 point on bread-loafed III lumpectomy specimens: sensitivity 100% and specificity 87% on homogeneous samples, sensitivity 70% and specificity 70% on full dataset Intraoperati N=175 MarginProbe Assess Even with a limited point ve blinded System Probe & intraoperative sampling by the device, study - MarginProbe performance on per-patient detection rate phase II System Type 1.0 the resection is superior with 6/2006 – system console surface of Device+SOC (73%) as V 5/2008 lumpectomy compared to SOC alone specimens and (46%) evaluate adjunctive device contribution to SOC Pilot N=300 MarginProbe Assessment of - Device is safe for Study System Probe device detection intraoperative use 11/2006 – & performance and - Re-excision rate is 11/2007 MarginProbe clinical utility in reduced by 56% System Type a randomized, (p=0.0027) 1.0 system controlled - Positive margin console (patient is identification guiding blinded), intraoperative resection is intended use superior in Device+SOC MAST fashion. Assess arm (60%) compared to cosmetic SOC (41%) outcome - Cosmesis is not affected associated with by device use device use - Excised tissue volume is compared to not affected by device SOC. - Performance is the same for both palpable and non-palpable lesions