ISI Background Information for 042415 FDA Meeting_final

CONFIDENTIAL ISI-FDA MEETING April 24, 2015

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Background Information for April 24, 2015

Meeting between the FDA and Intuitive Surgical, Inc.


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Intuitive Surgical, Inc. (ISI) greatly appreciates the opportunity to discuss with the FDA current topics of

interest regarding the da Vinci Surgical System (hereinafter da Vinci System). This document is

provided as background for the meeting between ISI and FDA representatives.

The purpose of the meeting is to open up lines of communication between ISI and FDAs postmarket

surveillance and da Vinci Working Group staff and to aid FDA in performing its postmarket surveillance

duties by:

Sharing significant postmarket clinical data on da Vinci System,

Reviewing MDR death and serious injury report rates in the context of report date vs.

occurrence date,

Reviewing unique factors that influence complaint reporting to ISI, and

Discussing most productive ways to work together in getting the Agency the postmarket

information it desires.

Provided below is an executive summary of the background information regarding the planned agenda

topics followed by a more detailed discussion.

Executive Summary

The da Vinci System was designed to address the technical limitations of conventional

laparoscopy using computation, mechatronics, 3D imaging technology, and control algorithms

to allow surgeons to apply minimally invasive surgery techniques to a broader population of

patients, and to improve the experience of minimally invasive surgery for patients and surgeons.

The da Vinci System is commonly used in the United States. The system was used in over

570,000 procedures globally in 2014.

Robust review of postmarket data includes both the analysis of MDR trends and the continuous

monitoring of clinical literature.

Large scale, high Level of Evidence studies for procedures performed using the da Vinci System

consistently demonstrated superior patient safety as compared to open and laparoscopic

surgical techniques.

o Clinical literature also supports superior patient safety of the da Vinci System as

compared to open surgery independent of patient selection and surgeon experience.

o Clinical literature on post-discharge readmission rates in prostatectomy and

hysterectomy supports lower readmission rates for da Vinci surgery than laparoscopic or

open surgical techniques.

Complaint reporting on da Vinci devices is unique due to the comprehensive nature of da Vinci

assisted surgery, case attendance by ISI representatives, media attention, and extensive

advertising and recruiting by the plaintiff lawyer community.


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The types of reported complications for da Vinci assisted surgery are the same as with other

types of surgery.

The complaint investigation process at ISI is thorough, timely, responsive to FDAs AI requests,

and designed to be in compliance with regulatory requirements.

ISI wishes to work collaboratively with the FDA and aid the FDAs postmarket surveillance

efforts.

Background

I. Overview of Intuitive Surgicals da Vinci System

ISI developed the da Vinci System to satisfy a need in surgery to broaden use of minimally invasive

approaches and to improve the experience of minimally invasive surgery for patients and surgeons.

Conventional minimally invasive surgery (laparoscopy) advanced relatively quickly in minimizing

morbidity and complications in several surgical procedures, particularly those that required relatively

little surgical reconstruction (for example, cholecystectomy to treat gallbladder disease, endometriosis

resection, and so on). Application of minimally invasive techniques for more complex pathology (e.g.

surgery to treat cancer) and those procedures that require significant reconstruction (e.g. pelvic floor

reconstruction) had proceeded significantly more slowly. For example, in the year 2000, approximately

95% of all prostate cancer surgery was performed through an open incision.

The primary technical limitations of conventional laparoscopy when compared to open surgery are four-

fold:

Most laparoscopic surgery is performed using a two-dimensional image, which inhibits depth

perception.

Movement of long, rigid tubular instruments in laparoscopy is subject to direction reversal due

to the pivot of the instrument at the patients body wall and surgeon tremor, which makes fine

instrument movement challenging.

Most laparoscopic instruments do not have the same freedom of motion as a human wrist

inside the body, which constrains the angles at which these instruments can approach tissue.

The challenging ergonomics associated with conventional laparoscopy can be physically

detrimental to the surgeon.

The da Vinci System was designed to address the above limitations using computation, mechatronics,

and control algorithms. The system incorporates three-dimensional digital cameras and displays to

provide an immersive 3D view of the surgical field for the surgeon, enhancing depth perception. The

system uses mechatronic arms to hold and control the instruments, and uses computational algorithms

to provide the surgeon intuitive control of these instruments. It uses tubular surgical instruments that

incorporate distal wrists that retain the patient benefits of port access while returning to the surgeon

the two degrees of freedom of their wrist that were lost in the transition from open surgery to manual


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laparoscopy. Finally, surgeons are able to operate seated in a comfortable, ergonomic position. The

combination of these improvements in visualization, wristed instruments, mechanisms, computer

control, and ergonomics increases the precision and control of the instruments compared with manual

laparoscopy. Table 1 below summarizes these key differences.

Laparoscopy Technical

Limitation

da Vinci System Solution Benefit conferred

Two-dimensional image Three-dimensional image Strengthens depth perception due to

additional visual information

Counter intuitive movement Intuitive movement afforded by

mechatronic arms and computational

algorithms

Greater precision and control at tool

tips for fine tasks like suturing and

reconstruction

Long, rigid tubular instruments Wristed tubular instruments Returns to surgeon the ability to reach

around structures that was lost in

transition from open surgery to

laparoscopy

Poor ergonomics Improved ergonomics Less neuropathies and musculoskeletal

problems from high force laparoscopic

manipulation, less mental stress and

workload

Table 1. How the da Vinci System Addresses Key Technical Limitations in Laparoscopy


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Figure 1 below shows the key system elements. The da Vinci is comprised of a Surgeons Console and

optional dual Surgeons Console (for training), a Patient Side Cart, and an Imaging System (Vision)

Tower.

Figure 1: da Vinci Surgical System

The da Vinci System includes:

mechatronics and computational algorithms that allow surgeons to intuitively control wristed

laparoscopic instruments,

3D imaging that displays combined left and right eye images to the surgeon, and

a suite of instruments and accessories that can perform the same surgical tasks as manual

laparoscopy (e.g. scissors, needle drivers, cautery instruments).

The da Vinci System is NOT:

an autonomous robot it does not take any surgical action on its own, nor

a clinical decision maker there is no attempt to replace surgeon judgment.

As surgical robotics was more broadly adopted, the need for key technologies available in open and

laparoscopic surgery was requested for the robotic product lines. This included vessel sealing, stapling,

and single site instrument technology (all of which have been the subject of subsequent 510(k)

clearances). The additional technology has expanded the da Vinci product offering and has allowed ISI

to better support its customers requests.

Surgeons Console Patient Cart Vision Tower


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II. Review of Postmarket Data - Summary of Significant Clinical Literature

on da Vinci Assisted Surgery

The da Vinci System is a surgical tool that can be used for a variety of surgical procedures. By the end of

2014, over 3,000 systems were in clinical use worldwide, with approximately 570,000 procedures

completed in 2014. The primary surgical specialties using the system in 2014 were gynecologic surgery,

urologic surgery, general surgery, thoracic surgery, head and neck surgery (otherwise known as

transoral robotic surgery or TORS), and cardiac surgery. The approximate breakdown in procedures for

these specialties for 2014 worldwide is shown in Table 2.

Surgical Specialty Approximate Procedures in 2014

Total 570,000

Gynecology 252,300

Urology 173,200

General Surgery 120,660

Thoracic 11,700

Head Neck (TORS) 6,800 Cardiac 4,600

Table 2: 2014 Breakdown of Procedures by Specialty

The peer-reviewed clinical literature on the da Vinci System is extensive and diverse. There are over

8,500 peer-reviewed clinical publications on the use of the da Vinci System across many specialties and

patient populations with new publications on the da Vinci System releasing at a rate of approximately

150 per month. ISI-sponsored or supported1 research constitutes less than 1% of these publications.

There are now greater than 1,250 high Level of Evidence (LOE) comparative studies of the da Vinci

System. Clinical literature provides critical data for the ongoing surveillance of postmarket product

performance.

Analyses of the da Vinci System presented in the clinical literature span a variety of topics including

clinical outcomes, surgeon and OR staff training, and cost. The maturity of literature describing the use

of the da Vinci System varies by surgical specialty; for instance, the data for da Vinci assisted procedures

in urology and gynecology are more extensive with higher LOE as compared to general surgery in which

the da Vinci System has more recently been adopted. Therefore, much of the analysis presented here

will stem from publications2 encompassing the most mature specialties that have been well adopted in

1 ISI sponsored or supported literature refers to studies to which ISI contributed funds or data analysis support for

the study. 2 For all articles referenced in this document, full text articles are attached.


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the market and thus providing studies with large sample size and high LOE. A review of papers for

representative procedures in Thoracic, General Laparoscopy, and TORS are also included to provide the

published data supporting the safety of da Vinci for these additional general cleared indications.

The scientific LOE for clinical publications is determined based on ISIs interpretation of The Oxford

Levels of Evidence (March 2009) [1], as provided in Table 3 below.

Level Sublevel Study Design

I

a Systematic reviews of Randomized Control Trials (RCTs)

b Randomized Controlled Trials (RCTs)

c RCTs investigating robotic technique

II

a Systematic reviews of comparison studies

Independent database population studies

b Prospective, non-randomized studies

RCTs where N


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incontinence rate, erectile dysfunction rate, positive surgical margin rate (cancer), blood transfusion

rate, and operative time.

Overall Summary of Prostatectomy Data

Data from the larger and higher LOE studies comparing da Vinci assisted prostatectomy with

open prostatectomy demonstrate that use of the da Vinci System in prostatectomy is superior

to open surgery in key measures of safety and effectiveness:

Reduced rate of blood transfusions [2-11]

Reduced length of stay [3-7, 10, 11]

Lower mortality rate [3, 5, 6, 10]

Fewer overall complications [2, 3, 5-7, 9-11]

Reduced rate of urinary incontinence [7, 12]

Reduced rate of erectile dysfunction [7, 13]

Lower overall and T2 positive surgical margin rate [7, 10]

Some of these studies also indicate a longer operative time to perform a da Vinci assisted

Prostatectomy compared to open surgery:

Longer Operative Time [3, 6, 7, 9]

Detailed analysis

A complete review of the large set of comparative prostatectomy studies was conducted, and is

summarized below in Table 4. Two of the largest database studies with strong LOE were

completed by Kowalczyk [5] and Liu [6]

on the clinical outcomes of prostatectomy using the da

Vinci System. These studies demonstrate that, while use of the da Vinci System increased

operative time compared to open prostatectomy by averages ranging from 15.8 to 60 minutes,

da Vinci assisted prostatectomy was definitively safer than the open surgery it replaced with

respect to the key measures summarized above. Effectiveness was also improved relative to

open surgery as demonstrated by lower average overall positive surgical margin rates [10],

lower T2 positive margin rates [7, 10], improved urinary continence [7, 12], and improved

erectile function [7, 13]. Results from these studies are consistent with results demonstrated in

the extended body of literature on da Vinci use in prostatectomy and are summarized in Table 4

and Table 5.


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Key Safety

Parameters

2013 Davis[3]

LOE (IIa)

2013

Pilecki[9]

LOE (IIa)

2013

Moran[7]

LOE (IIa)

2012 Tewari[10]

LOE (IIa)

2012

Novarra[8]

LOE (IIa)

2009 Hu[4]

LOE (IIa)

2011

Kowalczyk[5]

LOE (IIa)

2012 Trinh[11]

LOE (IIa)

2013 Liu[6]

LOE (IIa) 2014 OHTAC HTA[2]

10

LOE (IIa)

Study Details

N=57,472

Premier

Database

(ISI provided

data analysis)

N=5,471

NSQIP

Database

(Independent

of ISI)

Systematic

Review

9-20 studies

(Independent

of ISI)

Systematic

Review

400 studies

(ISI provided

data analysis)

Systematic

Review

110 studies

(Independent

of ISI)

N=8,837

SEER Database

(Independent of

ISI)

N=78,232

CMS Database

(Independent of

ISI)

N=14,987

CMS Database

(Independent of

ISI)

N=5319

NSQIP Database

(Independent of

ISI)

Ontario HTA Population based,

retrospective cohort study

design

(Independent of ISI)

Overall

complication rate*

10.6% vs.

15.8%

(p


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Key

Effectiveness

Parameters

2013 Davis1

2013

Davis[3]

LOE (IIa)

2013 Pilecki2

2013 Pilecki[9]

LOE (IIa)

2013 Moran3

2013 Moran[7]

LOE (IIa)

2012 Tewari4

2012 Tewari[10]

LOE (IIa)

2012 Novarra,

Ficarra11,12,13

2012 Novara,

Ficarra[12-14]

LOE (IIa)

Study Details

N=57,472

Premier

Database

(ISI provided

data analysis)

N=5,471

NSQIP Database

(Independent of

ISI)

Systematic Review

9-20 studies

(Independent of

ISI)

Systematic Review

400 studies

(ISI provided data

analysis)

Systematic Review

110 studies


Length of Stay

2.2 days vs.

3.4 days*

(USA)

(p


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Hysterectomy To date, there are approximately 420 cancer hysterectomy and 195 benign

hysterectomy peer-reviewed publications examining use of the da Vinci System in hysterectomy

procedures. Of these, more than 125 cancer and 60 benign studies compared da Vinci assisted

hysterectomy with other surgical methods (e.g. open, laparoscopic).

Safety and effectiveness in hysterectomy procedures are summarized below with respect to the

following parameters: length of stay (total and prolonged), readmission rate, complication rate, blood

transfusion rate, conversion rate, and operative time.

Overall summary of the data

Hysterectomy for Cancer- Data from larger and higher LOE studies comparing da Vinci assisted

cancer hysterectomy with open surgery demonstrate that use of the da Vinci System in cancer

hysterectomy is superior to open surgery in the following key measures of safety:

Fewer complications [15, 16]

Fewer blood transfusions [17]

Shorter length of stay [15, 18, 19]

These studies also indicate a longer operative time to perform a da Vinci assisted cancer

hysterectomy than open surgery:

Longer operative time [15, 16, 19, 20]

The longer operative time was not associated with an increased complication rate. As noted

above, there were actually fewer complications in the da Vinci group.

Hysterectomy for Benign Conditions - Data from large and high LOE studies comparing da Vinci

benign hysterectomy with open and laparoscopic surgery demonstrated that use of the da Vinci

System in benign hysterectomy is superior to open and laparoscopic surgery in several key

measures of safety and effectiveness:

da Vinci versus Open

Fewer complications [15, 21-25]

Fewer re-admissions at 30 days [23]

Fewer blood transfusions [15, 21,

22, 24]

Shorter length of stay [15, 21-25]

da Vinci versus Laparoscopic

Fewer complications [22, 23, 26]

Fewer re-admissions at 30 days [23]

Fewer conversions to open surgery [21, 22,

26]

These studies also indicate an equivalent or longer operative time to perform a da Vinci benign

hysterectomy as follows:


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Longer operative time[15, 21, 22,

25]


Varied differences in operative time

Detailed analysis Hysterectomy (for Cancer or Benign conditions)

A thorough review of the large set of comparative hysterectomy studies was conducted, as

summarized below in Tables 6 - 8. The largest of these studies, by Luciano [22], involved use of

a national database (Premier) and large sample size (N=289,875). The study demonstrated that

while use of the da Vinci System increased operative time compared to open and laparoscopic

benign hysterectomy, da Vinci assisted hysterectomy was definitively safer with respect to the

key measures of complication rate (open and laparoscopic), blood transfusion rate (open),

length of stay (open), and rate of conversion to open (laparoscopic). The data are consistent

with the results of the next largest study, by Martino [23] et al., which demonstrated that

patients who underwent a da Vinci assisted hysterectomy were less likely to be readmitted

within 30 days as compared to open (1.0% vs. 3.5%) and laparoscopic (1.0% vs. 2.58%)

hysterectomy. Results from these studies are consistent with results demonstrated in the

extended body of literature on da Vinci used in hysterectomy.


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Key Safety

Parameters

2010

Matthews[2

4]

LOE (IIIb)

2011

Landeen[21]

LOE (IIIb)

2013

Martino[23]

LOE (IIIb)

2014

Woelk[25]

LOE (IIIb)

2011

OSullivan[1

5]

(mixed

benign,

cancer)

LOE (IIa)

2014

Luciano[22]

LOE (IIa)

Study Details

N = 277

Single

Institution

(Independent

of ISI)

N = 843

Single

Institution

(ISI sponsored

study)

N=1,795

Single

Institution

(Independent

of ISI)

N=468

Single

Institution

(Independent

of ISI)

Ireland HTA

Systematic

Review

17-22 studies

(Independent

of ISI)

N=289,875

Premier

Database

(ISI provided

data analysis)

Overall

complication rate*

4.29% vs.

23.04%

(p


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Key Safety

Parameters

2011

Scandola[26]

LOE (IIa)

2013

Rosero[17]

LOE (IIa)

2013

Wright[27]

LOE (IIa)

2013

Martino[23]

LOE (IIa)

2011

Landeen[21]

LOE (IIIb)

2014

Luciano[22]

LOE (IIa)

Study Details

Systematic

Review

21 comparison

studies

(Independent

of ISI)

n = 15,576

NIS Database

Propensity

matched

(Independent

of ISI)

n = 9942

Premier

Database

Independent

of ISI

N=1,795

Single

Institution

(Independent

of ISI)

N = 843

Single

Institution

(ISI

sponsored

study)

N=289,875

Premier

Database

(ISI provided

data analysis)

Overall

complication

rate*

PostOp

Comps

Lap rate 1.8x

higher than da

Vinci

(p


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Key Safety

Parameters

2010 Gaia[20]

LOE (IIa)

2010 Reza[16]

LOE (IIa)

2011

OSullivan[15]

(mixed benign and

cancer)

LOE (IIa)

2012 Geetha[18]

LOE (IIa)

2012 ONeill[19]

LOE (IIa)

Study Details

Meta analysis

8 studies

(Independent

of ISI)

Meta analysis

22 studies


Ireland HTA

Systematic review

17-22 studies


Meta analysis

12 studies

(Independent of

ISI)

Meta analysis

21 studies

(Independent of

ISI)

Overall

complication

rate*

Wound

Comps

1.8% vs.

13.7%

(p =0.01)

da Vinci rate 78%

lower than open

(p


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Additional Surgical Safety Data (draft manuscript, pending submission)

To further investigate complication rates, data from the Premier Database for hysterectomy procedures

for benign indications using open, vaginal, laparoscopic, and da Vinci assisted surgical techniques

performed over a 6 year period (2008-2013) were analyzed for demographic and clinical information as

well as perioperative outcomes for a total of 386,991 procedures. This analysis was performed by ISI

and the data are not yet published. The outcomes reported include perioperative information from the

hysterectomy procedure and initial hospitalization only; no post-discharge complications or

readmissions are included. Overall, da Vinci surgery had statistically significant fewer complications

versus open and laparoscopic methods, as summarized below. There were no statistically significant

differences in favor of the other surgical techniques over da Vinci assisted surgery.


Fewer Intra-op complications

Fewer Intra-op transfusions

Fewer Post-op complications

Fewer Post-op transfusions


Fewer Intra-op complications

Fewer Intra-op transfusions

Fewer Post-op complications

Fewer Post-op transfusions

Figure 2: Comparison of surgical safety da Vinci vs. open and laparoscopic benign

hysterectomy in a large database review pending submission

0

2

4

6

8

10

12

14

16

18

20

Intra Op CompIntra Op Blood

Transfusions

Post Op Comp Post Op Blood

Transfusions

Ra

te (

%)

Open (N=148,296)

Laparoscopic (N= 154,907)

da Vinci (N= 83,788)


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Conclusion Overall safety and effectiveness of da Vinci Surgery is equivalent or better than

open and laparoscopic surgical approaches, as demonstrated by large and high LOE studies.

Surgical Safety Data in Additional Procedures

Thoracic - In 2013, Kent et al. [28] published a scientific LOE IIa study in the Annals of Thoracic

Surgery comparing Open Surgery, Video Assisted Thoracic Surgery (VATS) and da Vinci assisted

thoracic surgery. The data used in the analysis were pulled from the HCUP SID database and

included an analysis of a propensity matched patient cohort that included n=1,233 for each

Open and VATS surgical approaches and n=411 for da Vinci assisted surgery. As seen in Figure 3

below, da Vinci assisted thoracic surgery showed statistically significant better results over open

thoracic surgery relating to lower mortality rate (p=0.016), lower overall complication rate

(p=0.003), shorter length of stay (p


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General Laparoscopy (Colorectal) In 2014, Xiong[29] et al published a meta-analysis in Journal

of Gastrointestinal Surgery comparing da Vinci assisted total mesorectal excision for rectal

cancer (RTME) to laparoscopic (LTME). Eight studies were identified that included 1229 patients

in total, 554 (45.08 %) in the RTME group and 675 (54.92 %) in the LTME group. Compared with

LTME, RTME was associated with lower conversion rate (p=.0004), lower positive rate of

circumferential resection margins (p=.04) and lesser incidence of erectile dysfunction (p=.02).

Operation time, estimated blood loss, recovery outcome, postoperative morbidity and

mortality, length of hospital stay, number of lymph nodes harvested, distal resection margin

(DRM), proximal resection margin (PRM), and local recurrence had no significant differences

between the two groups. The results demonstrated that da Vinci assisted rectal surgery has

improved outcomes than laparoscopy with a similar safety profile.

Table 9: Summary of primary outcomes da Vinci assisted rectal surgery (RTME) versus

laparoscopic surgical methods (LTME) (Xiong et al., level IIa, independent of ISI)


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Trans Oral Robotic Surgery (TORS) - In 2014, M Chen et al. [30] published a scientific LOE IIa

study in Otolaryngology Head and Neck Surgery comparing open trans oral surgery for

oropharyngeal cancer versus TORS. The data used in the analysis were pulled from the NCDB

database and included n=4,269 for open and n=877 for TORS. As seen in Figure 4 below, The

TORS approach showed a statistically significant reduction in positive margin for TORS versus

open surgery (p


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location (urban or rural), and median annual caseload were also reported. Both cohorts were

propensity score matched by patient characteristics (age, race, CCI, year of surgery, and

insurance status) and by hospital characteristics (volume, location, region, and academic status).

Post propensity score matching, the open and da Vinci patient cohorts were similar with respect

to age and CCI, and the standardized differences between the two groups in patient and hospital

characteristics were 2 days Overall complications Mortality

Ra

te (

%)

da Vinci (n=7598)

Open (n=7389)


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sample, perioperative outcomes were superior in the da Vinci assisted cohort for key measures

of safety including blood transfusion rate, prolonged length of stay (> 2 days), overall

postoperative complication rate, and mortality rate.

Clinical studies support lower readmission rates for da Vinci surgery in comparison to open and

laparoscopic surgery

Prostatectomy - Pilecki[9]: In 2013, Pilecki et al. published a scientific LOE IIa study in the Journal

of Endourology comparing, among others, rates of readmission within 30 days and overall

complications of da Vinci assisted vs. open surgery for radical prostatectomy. The data used in

the analysis were pulled from the NSQIP database and included a large sample size (n=5,471)

across multiple institutions.

The study found statistically lower rates of readmission within 30 days and overall complications

in procedures completed with da Vinci compared to open surgery, as shown in Figure 6.

Figure 6: Comparison of readmission and overall complication rates da Vinci vs. open

prostatectomy (n=5,471, NSQIP database, level IIa, independent of ISI)

Hysterectomy - Martino [23]: In a 2014 study of 2,554 patients published in the Journal of

Minimally Invasive Gynecology by Martino et al., use of the da Vinci System was associated with

a lower readmission rate within 30 days compared to open abdominal, vaginal, and laparoscopic

methods of hysterectomy (Figure 7).

0

5

10

15

20

25

Readmission


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Figure 7: da Vinci Hysterectomy reduced readmission rate over open, laparoscopic and

vaginal (n=2,554, Single institution retrospective, IIIb, independent of ISI)

Conclusion: Studies published in the prostatectomy and hysterectomy clinical literature indicate

use of the da Vinci System is associated with lower rates of hospital readmission than open and

laparoscopic surgery.

Clinical Studies show fewer complications during the learning phase of da Vinci surgeons as compared

to complication rates of experienced surgeons using other surgical approaches

Prostatectomy - Using an outcomes database (Premier the same database used by Wright et.

al. JAMA[27]), surgeons and ISI evaluated the prevalence of complications as a function of the

introduction of the da Vinci System into surgical practice in prostatectomy and hysterectomy.

Given the maturity of prostatectomy using the da Vinci System, this procedure was studied first.

In an article published in the Journal of Endourology by Davis [3] and ISI, the authors found that

surgeons have fewer complications in their early da Vinci experience than surgeons with mature

experience performing open surgery. Figure 8 below shows the complication rate of learning

surgeons using da Vinci compared to surgeons with mature experience performing open

surgery. The evidence supports that the first cases using da Vinci in prostatectomy are

0

0.5

1

1.5

2

2.5

3

3.5

4

da Vinci

(n=601)

Laparoscopic

(n=427)

Open

(n=1194)

Vaginal

(n=332)

da Vinci

(n=601)

Laparoscopic

(n=427)

Open

(n=1194)

Vaginal

(n=332)


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associated with fewer complications than open surgeries performed by surgeons with mature

experience. This supports our view that training on the da Vinci System is effective and that da

Vinci can offer benefits to patients, even when the surgeon is early in the learning curve.

Figure 8: Complication Rates for Learning Surgeons using da Vinci Compared with Experienced

Surgeons Performing Open Prostatectomy

Hysterectomy - A similar analysis using the Premier Database was performed by Luciano [22]

and ISI evaluating complications of hysterectomy when surgeons are early in their da Vinci

experience compared to experienced surgeons performing open hysterectomy, laparoscopic

hysterectomy, and vaginal hysterectomy. The authors found that complications after

hysterectomy were lower for da Vinci surgery than any other surgical technique. Figure 9 below

shows the complication rate for hysterectomy with surgeons early use of da Vinci compared to

experienced surgeons performing open surgery, laparoscopy, and vaginal surgery. The evidence

supports that the first cases using da Vinci in hysterectomy are associated with fewer

complications and conversions than experienced surgeons performing any of the alternative

surgical approaches. Again, this analysis supports the view that training on the da Vinci System

is effective and that da Vinci assisted procedures can offer benefits to patients, even when the

surgeon is early in the learning curve.

6%

7%

8%

9%

10%

11%

12%

13%

14%

15%

16%

1-25 26-50 51-75 76-100 101-125 126-150

Co

mp

lica

tio

n r

ate

Groups of cases

Da Vinci Complication Rate by Increasing Experience

Mature Open Complication Rate


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Figure 9: Learning Curve Measures as a Function of da Vinci Surgery Experience

Bars are da Vinci rates or time by experience tranche (legend above, e.g., 1-25 cases,

26-50 cases, etc.)

The horizontal lines are measures for laparoscopy, open surgery and vaginal surgery,

as applicable, performed by experienced surgeons

Conversion means the rate of conversion from the intended approach (lap or da Vinci)

to open surgery

Conclusion: The results of these two studies indicate use of the da Vinci System is associated

with lower complication rates and (where applicable) conversion rates than the alternative

surgical approaches, irrespective of where a surgeon is on the learning curve for the da Vinci

System.


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III. Review of Postmarket Data - Unique Factors that Influence Complaints

to ISI

There are unique factors that influence complaint reporting to ISI. These key factors are summarized

below.

1) The comprehensive nature of the da Vinci System

ISI provides institutions with a broad product suite that includes cameras, instruments,

accessories, system hardware and software, along with extensive product training. In many

institutions it has become commonplace to refer to da Vinci surgery and non-da Vinci

surgery. As a result, when da Vinci is used in surgery, there is a strong association between the

devices and the procedure, which we believe results in more communication to the company

about issues encountered, regardless of whether a product malfunctioned or there was a causal

or contributory relationship between the device and the adverse event.

2) The da Vinci System brand recognition

Open and laparoscopic surgeries are performed with an assortment of devices from various

manufacturers. Thus, we believe that adverse events that occur in open or laparoscopic surgery

are much less likely to be reported to the manufacturer unless specifically related to that

manufacturer's product (e.g. a stapler that misfired). For example, consider two equivalent

cases of ureteral injury during a hysterectomy, one using da Vinci and one using laparoscopic

instruments. In both cases, there is no evidence that the devices either caused or contributed

to the injury, however it is likely that ISI would receive a report of the adverse event and

subsequently file it as an MDR. In contrast, it is likely that none of the manufacturers of the

multiple devices used in the laparoscopic procedure would be informed of the adverse event.

3) The significant campaign for da Vinci plaintiff recruitment

In 2013, ISI received a significant increase in legal complaints (complaints received from

plaintiffs attorneys), due to an aggressive ad campaign promoted towards all da Vinci patients.

This activity resulted in thousands of unsubstantiated claims reported into ISIs Postmarket

Surveillance team (see Figure 10 below). Due to the nature of these claims including limited

patient and event information provided by the attorneys, hospitals and surgeons unable to

provide further information due to pending litigation, and the MDR reporting timeline these

events were reported as MDRs since ISI did not have sufficient information to rule out a causal

or contributory relationship of the da Vinci System. To date, greater than two-thirds of these

cases have been voluntarily withdrawn by plaintiffs counsel on the grounds that they were non-

meritorious.


FOI Exempt 26

Figure 10: Chart reflecting the top 3 reporters of Serious Injury and Death MDR reports from

2011-2014

4) Case attendance and reporting by ISI representatives

On a daily basis, ISI representatives attend da Vinci assisted surgeries and are onsite at hospitals

to provide support. All ISI representatives are provided training on complaint handling and are

required to report any adverse event to the Postmarket Surveillance department as soon as

possible, regardless of whether the surgeon complained or suggested that the da Vinci System

caused or contributed to the event. Due to ISIs diligence in training and complaint reporting

awareness, combined with the daily onsite interactions at hospitals, ISI receives complaint

reports (including adverse events) from field representatives more often than hospitals or

health professionals (see Figure 10 above).

Due to the above noted unique factors, ISI believes that there is an increased likelihood that an adverse

event not directly related to a product problem will be reported to ISI after a da Vinci assisted procedure

as compared to a company associated with laparoscopic or open surgical devices. This places ISI in a

unique position with respect to receipt of reports of adverse events. We believe this difference in the

nature of complaint reporting to ISI does not derive from an inherent difference in device safety, as

evidenced by the summary of the clinical literature discussed above. Based on the below excerpt from

FDAs MAUDE database search page, ISI believes that FDA understands that there can be unique factors

that influence complaint reporting, and therefore, that MDR data alone is not sufficient to establish

rates of events or compare event rates between devices.

Although MDRs are a valuable source of information, this passive surveillance system has

limitations, including the potential submission of incomplete, inaccurate, untimely, unverified, or


FOI Exempt 27

biased data. In addition, the incidence or prevalence of an event cannot be determined from this

reporting system alone due to potential under-reporting of events and lack of information about

frequency of device use. Because of this, MDRs comprise only one of the FDA's several important

postmarket surveillance data sources.

MDR data alone cannot be used to establish rates of events, evaluate a change in event

rates over time or compare event rates between devices. The number of reports cannot be

interpreted or used in isolation to reach conclusions about the existence, severity, or

frequency of problems associated with devices.

Confirming whether a device actually caused a specific event can be difficult based solely on

information provided in a given report. Establishing a cause-and-effect relationship is

especially difficult if circumstances surrounding the event have not been verified or if the

device in question has not been directly evaluated.

MAUDE data does not represent all known safety information for a reported medical device and

should be interpreted in the context of other available information when making device-related or

treatment decisions.

IV. Review of Postmarket Data - MDR Data

ISI reviews all complaint and MDR data on a regular basis to look for trends or anomalies related to its

devices, procedure types, and other details of the events that may impact patient safety or product

quality. The number of individual Serious Injury and Death MDRs has increased due to the growing

volume of da Vinci assisted surgical procedures being performed worldwide. In addition, in 2013 there

was a dramatic increase in the number of MDRs filed as a result of complaints that were received from

plaintiffs attorneys (see Figure 10 and above discussion).

From 2013 to date, ISI has received over 3,500 attorney-sourced claims of events that have been

reported to the FDA as serious injuries. Greater than 99% of these claims have no product malfunction

allegation and of the 1% that have product allegation, these allegations have not been substantiated.

The claims are all for known complications of the given surgery.

The chart provided in Figure 11 below reflects the percentage of Serious Injury and Death MDRs

reported from 2011-2014 by the number of da Vinci assisted surgical procedures completed in that

same time frame. Importantly, this is presented by both report date and by event date. The large

increase of Serious Injury reports in 2013, when assessed by report date (red line in Figure 11), is solely

attributed to legal claims. When the same data are analyzed by the event date (purple line in Figure 11),

it can be seen that the significant spike in 2013 disappears.

To accurately evaluate device safety over time, the MDR trend data are best analyzed by event date and

not report date. When MDR serious injury and death data are analyzed by event date for the time


FOI Exempt 28

period seen below, there is no statistically significant change in death rates and the rate of serious

injuries have a statistically significant downward trend as per the Jonckheere Terpstra test (p


FOI Exempt 29

Figure 12: 2014 Death and Serious Injury MDRs by Procedure Category as Compared to all 2014

Completed Procedures by Category

In conclusion, the overall number of individual Serious Injury and Death MDRs has increased from 2011-

2014 due to the absolute volume of da Vinci assisted surgical procedures being performed; however,

the rate is unchanged (death) or improving (serious injury). Also, the overwhelming driving force for the

dramatic increase in 2013 was related to aggressive advertising campaigns by plaintiff attorneys. That

said, even with the legal claims included, there is a statistically significant decrease in the rate of serious

injuries over the last 4 years when assessed by event date. Also, ISI believes that MDR data are best

analyzed as rates by occurrence date and not report date. Other unique factors to ISI (discussed above)

also greatly impact the type and number of reports filed by ISI. As there is likely a higher likelihood of

common surgical complications being reported to ISI versus laparoscopic or open surgery device

manufacturers, MDR data is unlikely an ideal means of comparing adverse event rates among da Vinci

surgery, laparoscopic surgery and open surgery. Finally, due to the limitations and factors influencing

complaint and MDR reporting, ISI believes that well designed clinical studies are the best source of valid

scientific data to robustly evalute device safety and effectiveness and to compare safety and

effectiveness between surgical approaches.

V. ISIs Complaint Investigation Process

The Postmarket Surveillance department at ISI reviews, assesses, and investigates each complaint

individually within 24 hours of receipt. Information is gathered from all available sources for each case

to assist in determining the cause of the event. For Serious Injury and Death reports, information from

previous requests for additional information (AIs) from the FDA are always considered and addressed in

the MDR report to the extent the information is obtained during the investigation. In addition, all

2014 MDRs by Procedure Category 2014 Procedures Completed by Category


FOI Exempt 30

Serious Injury and Death reports are investigated by a medical professional and reviewed by an active da

Vinci surgeon.

Unfortunately, ISI encounters limitations outside of its control during the complaint investigation

process that may limit the amount of and type of information available about an event or patient. For

example, cases that are under active litigation may not be able to be discussed with the surgeon,

hospital, or other medical staff at the facility. In these cases, ISI typically has only partial information

provided by the attorney about a case. Even when a surgical complication is not yet the subject of

litigation, hospitals may fear litigation and refuse to release information or the device to ISI for analysis.

In these types of situations, due to the MDR timeline to report, the MDR may be submitted with very

little information and perhaps without a causal or contributory relationship to the device having been

established. Supplemental MDR reports are submitted whenever any additional information is

collected.

ISIs investigation process for these events includes reviewing all information available internally and

externally, including the following:

Internal Data External Data

System logs

Contacting all ISI representatives

involved with the account

Review of previous complaints

Data trends

Failure analysis information

Field support to gather information

ISI strives to provide robust, thorough, and timely complaint investigations to facilitate an understanding

and analysis of all reported events. When reporting MDRs, ISI considers the information typically asked

for by FDA in its AI requests and provides that information if such is available. Below is a list of

information that ISI always attempts to include in its MDR reports. If the MDR report does not include

this information, then that is because the information is not available to ISI.

Standard Investigation for Adverse Events

Attending Medical Professionals opinion of event

Patients operative / autopsy report(s)

Patients current and pre-existing condition(s)

Status on the return of suspect device (if applicable)

Internal ISI medical review and opinion of event

da Vinci System Log review

Multiple follow-ups for data collection

Contacting facility

personnel involved in

event


FOI Exempt 31

System Logs

As noted above, da Vinci System logs are reviewed as part of the complaint review process. System logs

are an additional source of information for the da Vinci System that is above and beyond what other

hand held device manufacturers have at their disposal. Due to the software and hardware of the da

Vinci System, some data related to system use can be collected and stored. These data are referred to

as system logs and include overall system status and error codes, the specific instruments used in each

procedure and pre-determined technical data. These data are stored on the System and transmitted

directly back to ISI, for sites that have a direct connection. Otherwise, the System logs are collected by

the field service personal at the next service visit and transmitted back to ISI at that time, which is

sometimes outside of the initial 30-day reporting window. System logs are commonly reviewed during

complaint investigations to correlate the specified device to the complaint (if applicable) or to

determine if any system information, data or error codes could be related to the specified complaint.

While system logs can be an advantageous tool in complaint investigation, they do have limitations. The

system logs are not immediately accessible for all systems, the logs do not detect every reportable issue,

and there are capacity limitations to how much information the logs can retain. The utility of system

logs will continue to grow and evolve, but in the meantime, system logs will remain only one piece to

our comprehensive complaint investigations.

VI. Conclusion and Future Collaboration

Since its introduction, the da Vinci System has been used safely and effectively in over 2.5 million

procedures worldwide to offer minimally invasive surgery to a broader population of patients and to

improve the experience of minimally invasive surgery for patients and surgeons. The da Vinci System is

now a common part of many surgical practices in the United States, including urologic and gynecologic

surgery. ISI continually monitors the postmarket performance of da Vinci technology through the review

of published clinical literature in addition to monitoring of its MDR data. The clinical evidence base

studying da Vinci use is extremely large and growing rapidly. The largest studies of da Vinci use show

that it provides significant improvements in safety and effectiveness when the comparator is open

surgery, and also shows benefits when compared with laparoscopy. Further analyses show that there

are lower readmission rates for da Vinci assisted surgery than laparoscopic or open and that the

complication rates for learning surgeons are lower than the experienced surgeons using the alternative

surgical methods being displaced. In the analysis of adverse events, it is shown that overall adverse

event rates are both low and stable or improving over a long period despite the increased use of plaintiff

attorney internet, cable and other advertising.

As an organization, ISI is committed to innovation and continuous improvement in both our products

and our processes to improve surgery. Furthermore, we are committed to maintaining a productive and

collaborative relationship with the FDA and wish to support FDAs postmarket surveillance efforts. ISI

believes that MDR data are best analyzed by occurrence date and with denominator information. ISI

also believes that assessment of safety in the postmarket setting should include consideration of data


FOI Exempt 32

from clinical trials. We look forward to our April 24, 2015 meeting with FDA where we can hopefully

discuss how best to get this important information to FDA to support FDAs postmarket surveillance

efforts with regard to the da Vinci Surgical System.


FOI Exempt 33

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Documents

ISI Background Information for 042415 FDA Meeting_final