INTERGEL Adhesion Prevention Solution Clinical Study of Use during Laparotomy for

Gynecologic Interventions Lifecore Biomedical, Inc.

FDA Clinical Perspective

Roxolana Horbowyj, MD

September 6, 2001

Outline

• Adhesions

• Adhesion Evaluation

• Clinical Studies

Pilot Study

Pivotal Study

• Summary

Adhesions• Form as a protective response to localize a peritoneal insult:

– Most commonly due to tissue trauma, foreign bodies, infection.

• May cause or minimize morbidity:– Prevent volvulus; contain bowel leaks

– Cause pain, bowel obstruction, female infertility

• May be characterized by: – Location: Direct (surgical site) / Indirect (remote site)

– Occurrence: De Novo (new) / Reformed (previously lysed)

– Extent

– Severity

There is no consensus on how to predict which peritoneal cavity adhesion(s) will cause morbidity / prevent morbidity.

Adhesion Evaluation

Consensus on how to best evaluate adhesion characteristics or how to best correlate adhesion characteristics with clinical outcome has not been reached.

• American Fertility Society (AFS) score

• Intergel Pivotal Study scores:– modified AFS (mAFS) score

– retrospective AFS (rAFS) score

AFS and Intergel Pivotal Study scores differ in:• Number of anatomic sites evaluated

• Method of anatomic site evaluation

• Method of determining the Final Score for a patient.

American Fertility Society (AFS) Score

• Developed in 1980’s by the American Fertility Society in an effort to address needs for a classification scheme for adnexal adhesions suspected to be associated with infertility.

• 4 anatomic sites evaluated:

– R-tube, R-ovary;

– L-tube; L-ovary

• Final AFS score for a patient is the score of the side with lower summed score. The higher score, representing the side with the higher adhesion burden, is dropped.

American Fertility Society (AFS) Score

AFS score per site Severity Extent0 none none

1 mild localized

2 mild moderate

4 mild extensive

4 severe localized

8 severe moderate

16 severe extensive

• Final AFS score range = 0 to 32– Tube and ovary scores are summed on each side.

– Final AFS score is the score of the side with the lower summed score.

American Fertility Society (AFS) Score

• Published, peer reviewed literature correlating AFS score to clinical outcome as to adhesions is scant.

• Published literature and its interpretation is often limited by – Small sample size

– Use of variations of the published AFS score, e.g.:

Different anatomic sites, e.g.: fallopian tubes only.

Different score assignments, e.g., 0 to 20.

• No consistent or validated correlation of AFS score to specific clinical findings has been demonstrated.

• Interobserver reproducibility at the level of 0.7 has been reported as observed in less than a third of surgeon pairs studied. (ref: Fertility and Sterility, vol. 62, no. 5, November 1994).

Modified American Fertility Score (mAFS)

• Developed for the Intergel pivotal clinical study to evaluate peritoneal adhesions.

• 24 pre-specified anatomic sites evaluated.

• Incidence, extent and severity: determined according to AFS score scheme except that the extent score is assigned as moderate for

• small bowel (site 5), • omentum (site 8)• right colon (site 9) and • left colon (site 10)

• Final mAFS score per patient is the average of 24 scores

• Final mAFS score range = 0 to 16

Modified American Fertility Society Score

012345678910111213141516

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24

# Sites with Adhesion

mA

FS

sco

re

Possible mAFS Score

Retrospective American Fertility Society Score (rAFS)

• Calculated from mAFS score incidence, extent and severity data.

• 10 mAFS site scores considered:

3 sites per each ovary: R and L

2 sites per each tube: R and L

• Extent: a single extent score calculated by taking the average of the extent numeric values from all sites making up the ovary or tube.

• Severity: a single severity score was assigned as the maximum of the anatomical site severities.

• Ovary and tube scores are summed on each side; the lower summed score is the retrospective AFS score per patient. The score representing the side with higher adhesion burden is dropped.

• Final rAFS score range = 0 - 16

Retrospective American Fertility Score Stratification

• Minimal 0 - 5

• Mild 6 - 10

• Moderate 11 - 20

• Severe 21 - 32

• None 0

• Minimum / Mild 1 - 10

• Moderate / Severe 11 - 32

• Minimum / Mild 0 - 10

• Moderate / Severe 11 - 32

Modified American Fertility Score (mAFS)Retrospective American Fertility Score (rAFS)

• mAFS score overlap confounds interpretation of a single score alone.

• The correlation of clinical outcome with an mAFS score or a change in mAFS score is not known.

• The correlation between the standard (4 site) AFS score and the retrospective (10 site) AFS is unknown.

• The correlation of clinical outcome with any AFS score stratification has not been validated.

Intergel

• 0.5% Ferric Hyaluronate Gel: an aqueous solution of sodium hyaluronate ionically cross-linked with ferric chloride.

Clinical Study Objectives

Pilot Study

To assess the methodology and to make a preliminary assessment of the safety of Intergel (300ml) compared to Lactated Ringers’ Solution (300ml) in patients undergoing peritoneal cavity surgery by laparotomy with a subsequent “second-look” laparoscopy.

Pivotal Study

To assess the safety and efficacy of Intergel (300ml) compared to Lactated Ringer’s Solution (300ml) in preventing or reducing adhesions in patients undergoing peritoneal cavity surgery.

Pilot Study: SummaryA prospective, randomized, single - center / single investigator study of 21

patients undergoing laparotomy for infertility with 6-12 week follow-up (2nd look) laparoscopy:

• 300cc of Intergel or Lactated Ringers Solution were left in the peritoneal cavity at the end of surgery.

• Adhesion incidence, extent and severity were evaluated at 18 pre-specified anatomic sites at baseline and at second look; an mAFS score was calculated retrospectively.

• At second look, difference between Intergel & control: mean mAFS = 4.65 mean adhesion incidence = 4.91

• At second look adjusted for baseline, difference between Intergel & control: mean mAFS = 4.12 mean adhesion incidence = 4.13

• Infection occurred in 1of 11 Intergel patients; 0 of 10 control patients.

Pivotal Study Design

• Prospective,

• Multi-center: 11 (12 proposed) US; 5 (6 proposed) Europe,

• Otherwise healthy 18 to 45 yo females with pain, bleeding or infertility, and adhesions at up to 11 of 24 pre-specified anatomic sites.

• Pre-operatively randomized: Intergel or LR Solution,

• Dose: 300 ml / patient, not adjusted for patient weight.

• Follow-up: labs at 7 days post-op

second - look laparoscopy at 6 - 12 weeks post-op

• Third party mask (proposed).

Pivotal Study Design

Safety Parameters

• Adverse Events

Efficacy Parameters

• Primary: Modified American Fertility Score (mAFS) based on 24 sites

• Secondary: Proportion of adhesions: number of sites with adhesions / number of

24 sites available

Adhesion incidence: yes / no

Adhesion extent: 0 (none), 1 (localized), 2 (moderate), 3 (extensive)

Adhesion severity: 0 (none), 1 (mild), 3 (severe)

Pivotal Study Design From pilot study data, the evaluable pivotal study cohort was expected to

demonstrate difference between Intergel and control group mean mAFS = 4.1: second look mean mAFS score adjusted for baseline.

Assumptions:

Loss to follow-up: 20% Intergel group; 10% control group

Loss to follow-up patients assigned mAFS score = 16 in Intent to Treat Analysis (ITT).

Therefore,

Clinically significant difference between Intergel and control group mean mAFS = 4.1 => 2.1 with adjustment for expected loss to follow - up (ITT).

Sample size, n = 180, to detect a difference of 2.1 in mean mAFS score, standard deviation = 5.0 for both groups, assuming ITT analysis.

Power = 80%; Significance level = 0.05.

Pivotal Study OutcomePatient Accounting

Total US Europe

I C I C

Design sample size: 180

#Enrolled (ITT): 281 102 98 41 40

# At second-look (EVL): 265 93 95 38 39

Lost to Follow-up: 9 3 3 1

% At second-look: 91.1% 96.9% 92.7% 97.5%

Data Sets:

ITT: Intent to Treat population

EVL: Evaluable population

Baseline Evaluation

Intergel and Control cohorts were clinically comparable within each continent. Comparing Europe and the US, cohorts

were clinically comparable for:

– Age, weight, labs

– Inclusion / exclusion criteria

were not clinically comparable for:

– Race

– Baseline adhesion incidence, mAFS or rAFS scores

– Procedure type, e.g.: adhesiolysis

Baseline Parameter:Race

US Europe

I C I C

n, ITT 102 98 41 40

% White 46.3 47.9 81.6 94.9

% Black 29.0 22.1 2.6 5.1

% Asian 1.1 4.2 7.9 0

% Latino 20.4 23.2 2.6 0

% other 3.2 3.2 5.3 0

Baseline Parameter:Mean Adhesion Evaluation

US Europe

I C I C

n, ITT 102 98 41 40

Incidence 2.49 2.27 6.00 6.40

Extent 0.20 0.19 0.47 0.54

Severity 0.28 0.21 0.58 0.65

mAFS 0.78 0.68 1.57 1.95

rAFS 1.55 1.80 4.27 5.20

Baseline Parameter: Patients with / without Adhesiolysis

US Europe

I C I C

n, ITT 102 98 41 40

n, Adhesiolysis 39 39 32 28

% 38% 40% 78% 70%

n, non-Adhesiolysis 63 59 9 12

% 62% 60% 22% 30%

Indications for Use

Current:

Intergel solution is a single use, intra-peritoneal instillate indicated to reduce the likelihood of developing moderate or severe post-operative adenexal adhesions in patients undergoing adhesiolysis or myomectomy during conservative gynecological pelvic surgery by laparotomy, when used as an adjunct to good surgical technique.

Intergel solution was also shown to reduce adhesion reformation to sites in addition to the adenexa, and adhesion formation at surgical sites, including the anterior abdominal wall.

“… likelihood of developing moderate or severe post-operative adenexal adhesions: rAFS = 11 to 32”

Intergel Control |Δ|*

N, EVL 131 134

rAFS = 11 to 32 at:

• Baseline 9 / 131 17 / 134 8 (5.8%)

• 2nd Look 0 / 9 7 / 17 7 (4.1%)

• 2nd Look 3 / 131 17 / 134 14 (10.3%)

• Baseline - 2nd Look 6 / 131 0 / 134 6 (4.5%)*Absolute difference between Intergel and Control

“… in patients undergoing adhesiolysis or myomectomy during conservative gynecological pelvic surgery by laparotomy …”

• rAFS scores were stratified into two groups: 0 - 10; 11 - 32.• Second - look data subgroups analysis were performed for:

– Myomectomy* – No myomectomy– Adhesiolysis*– Non-adhesiolysis– Tubal procedures– Ovarian procedures– Endometrial ablation

*Nominal statistical significance (p < 0.05) was noted for the myomectomy and adhesiolysis subgroups only.

… adhesion reformation to sites in addition to the adenexa …

Reformed Adhesions at Second - Look:

mean Intergel Control |Δ|* Scale**

n, EVL 131 134

Incidence 2.97 3.91 0.94

Total Possible 6.09 6.02 0.07

Proportion 0.46 0.66 0.20 0 - 1

Extent 0.82 1.32 0.50 0 - 3

Severity 0.94 1.47 0.53 0, 1, 3*Absolute difference between Intergel and Control

**Ordinate scales

… adhesion formation at surgical sites

Surgical Site Adhesions at Second - Look:

mean Intergel Control |Δ|* Scale**

n, EVL 131 134

Incidence 2.27 2.96 0.69

Total Possible 5.53 5.48 0.05

Proportion 0.39 0.50 0.11 0 - 1

Extent 0.64 0.97 0.33 0 - 3

Severity 0.78 1.14 0.36 0, 1, 3

*Absolute difference between Intergel and Control

**Ordinate scales

Safety: Infection RateUS Europe All |Δ|*I C I C I C

n 102 98 41 40 143 138

n, Infection 8 2 2 2 10 4 6

7.8% 2.0% 4.9% 4.9% 7.0% 2.9% 4.1%

Possibly 5 2 1 1 6 3 3

device related** 4.9% 2.0% 2.5% 2.5% 4.2% 2.2% 2.0% 2.9%

US

Data represents clean, non-malignant cases in 18 to 45 year old women: • Clean-contaminated / contaminated / dirty cases excluded intra-operatively• No malignant cases were enrolled.* Difference between Intergel and Control

**sum of Investigator and Independent assessment.

Summary• Device use was studied in clean class, non-cancer, gynecologic procedures

performed in 18 to 45 year old women with low baseline adhesion burden and otherwise in good health.

• Baseline evaluation differences between continents for race, adhesion evaluation and adhesiolysis were consistent with prospective criteria for non-poolability.

• Differences between Intergel and control cohorts for retrospective effectiveness outcomes: reformed and surgical site adhesions and difference in number and percentage of patients with moderate to sever adhesions at second look adjusted for baseline are clinically minimal in this study population.

• Infection rate was higher in Intergel treated patients than control: overall, and as “possibly device related” per investigator and independent assessment.

Increased infection rate in Intergel treated patients was driven by infection rate in US Intergel patients: 4.9% considered to be possible device related, compared to 2.0% in US control: a difference of 2.9%, which is clinically notable for young, healthy patients undergoing clean procedures.