rhBMP-2 soaked Absorbable rhBMP-2 soaked Absorbable Collagen Sponge (ACS) for the Collagen Sponge (ACS) for the treatment of Open Tibial Shaft treatment of Open Tibial Shaft

Fractures Fractures

Clinical SummaryClinical Summary

Points to consider

Clinical Summary of Clinical Summary of International InvestigationInternational Investigation

Clinical ReviewClinical Review

Study Design

Effectiveness

Safety

Clinical ReviewClinical Review

STUDY DESIGN

• Confounding Variables

• Patient Assessment

• Study Endpoints

• Data Analysis

Confounding VariablesConfounding Variables

• Technique for IM nail insertion• All fracture types considered equal• Isolated fractures grouped with

multiple injuries• Gustilo I ≠ Gustilo II ≠ Gustilo IIIA• Not all patients received a full

sponge to the fracture site• Large centers ≠ small centers

Distribution of Patients by Distribution of Patients by CountryCountry

Country # sites

Control .75 mg/ml

1.5 mg/ml

Total

Australia 6 18 18 12 48

Belgium/

Netherlands

8 8 12 12 32

Canada 4 5 10 15 30

France 4 8 6 11 25

Germany 12 35 22 26 83

Israel 4 5 13 10 28

Finland/

Norway

3 13 8 8 29

So.Africa 5 47 50 41 138

U. K. 3 11 12 14 37

TOTALS 49 150 151 149 450

Clinical Aspects of PoolingClinical Aspects of Pooling• Multiple centers • Over 50% of patients from 2 countries• Different experiences:

• Few patients from many sites pooled with many patients from few sites

• Different philosophies regarding optimal treatment :

reamed vs. unreamed nails• Different interpretations of healing, delayed

healing• Cultural and Geographic differences

• Applicability to US trauma populations

Assessment MethodsAssessment Methods

ClinicalFracture site tendernessRadiographic unionWeight bearing status

Independent Radiographic

Patient AssessmentPatient Assessment

PAIN

• No scale used for comparison

• Differentiation between fracture site tenderness and soft tissue injury difficult

Criteria For Radiographic Union for Criteria For Radiographic Union for Independent Radiology PanelIndependent Radiology Panel

A fracture was considered united when:• 3 of 4 cortices demonstrated cortical bridging

and/or complete disappearance of fracture lines• This definition includes:

• 3 of 4 cortices demonstrate bridging• 3 of 4 cortices demonstrated disappearance of fracture

lines• 2 of 4 cortices demonstrate cortical bridging and at least

1 of the remaining 2 cortices demonstrate disappearance of fracture lines

• 1 of 4 cortices demonstrated cortical bridging and at least 2 of the remaining 3 cortices demonstrated disappearance of fracture lines

Independent and Investigator Independent and Investigator ReviewReview

Gustillo Grade IIIA

Unreamed locked nail

0.75 mg/ml rhBMP

DefinitionsDefinitions

Healed Fracture:

• Absence of tenderness upon manual palpation of the fracture site

• Radiographic fracture union as assessed by the investigator

• Full weight bearing status

DefinitionsDefinitions

Delayed Union:

“A fracture is considered a delayed union if insufficient fracture healing was observed as determined by the investigators radiographic and clinical assessment”

Number of Patients with SI recommended & Number of Patients with SI recommended & Patients meeting criteria of Delayed unionPatients meeting criteria of Delayed union

SOC 0.75 1.5 Total

Total w/SI

41 28 24 93

# of criteria met3 criteria 12 18 7 24

(26%)

2 criteria 19 18 11 48(52%)

1 criterion

10 5 6 21(23%)

Primary EndpointPrimary Endpoint

Secondary Interventions :

How was the decision made?

Study Design:Study Design:Control GroupControl Group

What is the standard of Care?• Depends on

Fracture typeInjury severityBone lossContaminationConcomitant injuries

Different prognoses for different types

Relevance of EndpointsRelevance of Endpoints

Primary Endpoint• Rate of Secondary Interventions

– Recommended & Performed– Recommended & Not Performed– Not Recommended but Performed– Self Dynamizations (screw breakages)

Secondary Endpoints• Healing rate at 6 months• 50% probability of healing• CCRE

What is important?What is important?

• How many healed?

• What is the incidence of nonunion?

• What are the complications and incidence?

• Incidence of Infection?

• Time to healing for majority of the patients?

Combined Clinical & Radiographic Combined Clinical & Radiographic Endpoint Endpoint (CCRE)(CCRE)

• Independent review paired with investigator review

• Clinical assessment compared to purely radiographic assessment

• Patients with SI evaluated differently than patients without SI

Treatment of Missing Treatment of Missing DataData

• Inconsistent• Three examples

The DilemmaThe Dilemma

• Investigators unblinded

• Investigators determined pain, weight bearing status and radiologic healing

• Investigators determined when to perform secondary intervention

• The CCRE is 50% dependent on investigators determination

The DilemmaThe Dilemma• No time course/interval to delineate “delayed

healing” from “healing”

• No radiographic/clinical criteria to separate healing fracture vs. delayed healing

• How patients with delayed healing fractures were recommended for secondary intervention is imprecise.

• Extent to which all the investigators used the same criteria for determining a secondary intervention is unknown

ResultsResults

Effectiveness

• Primary Endpoint• Rate of Fracture Healing• Time to event Analysis• Probability of 50% healing• Nonunion

Primary EndpointPrimary Endpoint

Standard of Care

0.75 mg/ml rhBMP-2/ ACS

group

1.5 mg/ml rhBMP-2/

ACS group

SI 66

(44%)

51

(35%)

38

(26%)

Recommended

& Performed

38

(25%)

25

(17%)

19

(13%)

Exclude Self dynamization

31% 25% 21%

No SI 84

(56%)

98

(65%)

111

(74%)

Rate of Fracture HealingRate of Fracture Healing

Investigator Radiology Panel

SOC 0.75 mg/ml

1.5 mg/ml

SOC 0.75

mg/ml

1.5 mg/ml

26 wks

36 % 40 % 55 % 20 % 25 % 33 %

39 wks

48 % 51 % 64 % 38 % 41 % 50 %

50 wks

51 % 58 % 70 % 47 % 52 % 64 %

Probability of a Fracture Healing by Probability of a Fracture Healing by InvestigatorInvestigator

Time To Healing by InvestigatorTime To Healing by Investigator

Treatment Days to Healing Probability of Healing

Standard of Care 141 25%

184 50%

275 75%

0.75 mg/ml rhBMP-2/ACS

128 25%

187 50%

273 75%

1.5 mg/ml rhBMP-2/ACS

102 25%

147 50%

273 75%

Time to Independent Radiographic Time to Independent Radiographic Assessment of Fracture UnionAssessment of Fracture Union

Time to Fracture Healing by Independent Radiology Time to Fracture Healing by Independent Radiology PanelPanel

Treatment Days to Healing Probability of Healing

Standard of Care 189 25%

275 50%

351 75%

0.75 mg/ml rhBMP-2/ACS

186 25%

272 50%

351 75%

1.5 mg/ml rhBMP-2/ACS

182 25%

271 50%

353 75%

NonunionNonunion

SOC 0.75 mg/ml

1.5 mg/ml

Inv Rad Inv Rad Inv Rad

Overall

12 months

49% 53% 42% 48% 30% 38%

Patients w/ SI

12% 9% 13%

Time to Fracture healing by Investigator Time to Fracture healing by Investigator Assessment : Patients with Secondary Assessment : Patients with Secondary

InterventionsInterventions

SafetySafety

Serology• Anti-rhBMP antibodies• Anti Type I Bovine collagen antibodies

Hardware failure

Laboratory Results

Heterotopic Ossification

Infection

SerologySerology

Antibodies formed to:

Standard of Care

0.75 mg/ml rhBMP-2/ACS

1.5 mg/ml rhBMP-2/ACS

rhBMP-2 1

(1%)

3

(2%)

9

(6%)

Bovine Type I

Collagen

9

(6%)

22

(16%)

29

(20%)

Hardware FailureHardware Failure

SOC .75 mg/ml 1.3 mg/mlTotal Patients 32 (22%) 25 (17%) 16 (11%)

Total Events 48 33 25

Nail breakage 0 2 0

Screw Breakage

48 31 24

Pts reamed Nail screw breakage

7/39 (18%) 8/48 (17%) 2/59 (3.4%)

Pts unreamed nail screw breakage

25/108 (23%)

17/97 (18%)

14/86 (16%)

Laboratory resultsLaboratory results

Liver function Tests elevated in rhBMP-2 treated groups

• Elevated Amylase

• Hypomagnesemia

Heterotopic OssificationHeterotopic Ossification

SOC 0.75 mg/ml 1.5 mg/ml

Patients 4 5 8

Hypertrophic Callus

3 2 1

Soft tissue callus 0 1 2

HO of tibia fracture

0 1 0

Synostosis 1 0 1

Infection RateInfection Rate

SOC .75 mg/ml 1.5 mg/ml

Total 30% 23% 25%

Leg/Tibia 29% 25% 24%

Gustilo I 18% 17% 19%

Gustilo II 20% 19% 20%

Gustilo IIIA/B

48% 30% 33%

CONCLUSIONSCONCLUSIONS

• Definitions for assessment unclear• Assessments based on investigators• Clinical relevance of endpoints• Control group as standard of care an

issue• Pooling across different sites and

applicability to US population an issue• Outcomes Interpretations differ• Safety questions