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EUROPEAN AND AMERICAN OSTEOSARCOMA STUDY (EURAMOS1)
Need for international
collaboration in rare diseases
Supported by the European Science Foundation (ESF) under the EUROCORESProgram European Clinical Trials (ECT), through contract No. ERASCT-2003-980409 of the European Commission, DG Research, FP6
Stefan BielackCooperative Osteosarcoma Study Group
Klinikum Stuttgart - OlgahospitalPediatrics 5 (Oncology, Hematology, Immunology)
Stuttgart, [email protected]
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What is aWhat is arare rare
disease?disease?
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Rare Disease Act of 2002 (HR 4013)affects < 200,000 persons in the US (< .07% of US population)
European Commission on Public Health"life-threatening or chronically debilitating diseases which are
of such low prevalence that special combined efforts are needed to address them.”
low prevalence: < 5 / 10,000 in the community(< .05% of the overall population)
Rare Disease DefinitionRare Disease Definition
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Cancer in children & adolecents < 20 years of age
12,400 affected / year
Malignancies of the bone• average annual incidence rate 8.7 per million• about 6% of childhood cancer
=> 400 osteosarcoma+ 200 Ewing’s sarcoma.
rare disease: < 200,000 persons in the US
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Osteosarcomaage (years) incidence/10,000/year
5-9 .024 10-14 .06815-19 .084
rare disease: < 5 / 10,000
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Trial participation• young patients• high grade central OS• no primary mets• extremity primaries
Osteosarcoma
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• POG/CCG-INT0133 662 4.0 years 166/year Meyers, J Clin Oncol 2005&8
• EOI-80931 497 9.3 years 53/year Lewis, J Natl Cancer Inst 2007
• COSS-96 442 5.5 years 80/year Kempf-Bielack, SIOP 2008
• SFOP-94 234 7.0 years 33/year Le Deley, Eur J Cancer 2007
• SSG/ISG-I 181 3.5 years 52/year Ferrari, J Clin Oncol 2005
study n recruitment Reference
Recent Recent MultiinstitutionalMultiinstitutional Osteosarcoma StudiesOsteosarcoma Studies
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Do we need Do we need international international
collaboration ?collaboration ?
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61 100
0
10
20
30
40
50
60
70
80
90
100
present new miracle drug
Osteosarcoma Osteosarcoma 5 year survival5 year survival
Perfect FuturePerfect Future
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• Similar Regimens(AP) - MAP- (MAPI)
• Similar Results
• Progress Slow
• Similar Regimens(AP) - MAP- (MAPI)
• Similar Results
• Progress Slow
OsteosarcomaOsteosarcoma
RealityReality
37
58 59 61
0
10
20
30
40
50
60
70
1978-1982 1983-1987 1988-1992 1993-1997
Osteosarcoma: 5-year survival rates
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Salvage of poor Salvage of poor responders ?responders ?
Jahre
20181614121086420
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en
1,0
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Osteosarcoma: Response & Survival
good (n=734)
73.4% (SE 2%)
47.2% (SE 3%)
poor (n=586)
p<.0001COSS:Bielacket al 2002
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3 a EFS: good ≈≈≈≈ 75%
poor ≈≈≈≈ 50%
Salvage-Question Statistics
Salvage-Question Statistics
Osteosarcoma Osteosarcoma
EURAMOSEURAMOS
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3 a EFS: good ≈≈≈≈ 75%
poor ≈≈≈≈ 50%
Significance 5%Power 80%50% ⇒⇒⇒⇒ 60%
Salvage-Question Statistics
Salvage-Question Statistics
Osteosarcoma Osteosarcoma
EURAMOSEURAMOS
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3 a EFS: good ≈≈≈≈ 75%
poor ≈≈≈≈ 50%
Significance 5%Power 80%50% ⇒⇒⇒⇒ 60%
needed: ± 700 poor responders⇒ ±±±± 1400 patients
Salvage-Question Statistics
Salvage-Question Statistics
Osteosarcoma Osteosarcoma
EURAMOSEURAMOS
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• COG 166/year 8.4 years
group recruitment study duration
MultiinstitutionalMultiinstitutional Osteosarcoma Groups Osteosarcoma Groups
& Salvage Question& Salvage Question
POG/CCG-INT0133Meyers et al, J Clin Oncol 2005&8
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• COG 166/year 8.4 years
• COSS 80/year 17.5 years
group recruitment study duration
MultiinstitutionalMultiinstitutional Osteosarcoma Groups Osteosarcoma Groups
& Salvage Question& Salvage Question
COSS-96Kempf-Bielack et al, SIOP 2008
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• COG 166/year 8.4 years
• COSS 80/year 17.5 years
• EOI 53/year 26.4 years
group recruitment study duration
MultiinstitutionalMultiinstitutional Osteosarcoma Groups Osteosarcoma Groups
& Salvage Question& Salvage Question
EOI-80931Lewis, J Natl Cancer Inst 2007
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• COG 166/year 8.4 years
• COSS 80/year 17.5 years
• EOI 53/year 26.4 years
• SSG/ISG 52/year 26.9 years
group recruitment study duration
MultiinstitutionalMultiinstitutional Osteosarcoma Groups Osteosarcoma Groups
& Salvage Question& Salvage Question
SSG/ISG-IFerrari et al, J Clin Oncol 2005
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• COG 166/year 8.4 years
• COSS 80/year 17.5 years
• EOI 53/year 26.4 years
• SSG/ISG 52/year 26.9 years
• SFOP 33/year 42.4 years
group recruitment study duration
MultiinstitutionalMultiinstitutional Osteosarcoma Groups Osteosarcoma Groups
& Salvage Question& Salvage Question
SFOP-94Le Deley et al, Eur J Cancer 2007
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How can we How can we increase increase
recruitment ?recruitment ?
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• include adults too (challenging)
• include high grade surface OS (few)
• include resectable axial primaries(few)
• include resectable primary mets(10-15%)
Osteosarcoma: Increased recruitment
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recruitment max. + 20%
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• include adults too (challenging)
• include high grade surface OS (few)
• include resectable axial primaries(few)
• include resectable primary mets (10-15%)
Osteosarcoma: Increased recruitment
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Salvage question:
International, intergroupcollaboration necessary
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Intergroup collaborationIntergroup collaboration
CaveatsCaveats
• intergroup compromizes necessary
• additional infrastructure requirements
• more committees & agencies to please
• “worst” national regulation may apply for all
• no uniform funding
• less glory / investigator
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Intergroup collaborationIntergroup collaboration
ProPro’’ss• increased recruitment
=> quicker answers=> potential to address more questions
• synergy
- multiple areas of expertise- rapid knowledge exchange
• stronger “lobbying” power
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Pan-European/American Cooperation
EURAMOS / AOST 0331PanPan--European/American CooperationEuropean/American Cooperation
EURAMOS / AOST 0331EURAMOS / AOST 0331SSG
COG
EOI
COSS
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EURAMOSEURAMOS--1 / AOST 03311 / AOST 0331
aims
• investigation of
salvage therapy for poor responders(+/- HD-IFOS/ETO)
• investigation of
maintenance therapy for good responders(+/- pegylated interferon)
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4
5
5
5
8
8
9
10
11
16
21
33
61
82
305
0 50 100 150 200 250 300 350
NZL
NOR
FIN
DK
CH
ÖST
SE
H
BE
NL
AUS
CDN
UK
DE
USA
EURAMOS / AOST 0331 population (million)
583 million=
8.7% of world population
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5
6
6
6
10
10
11
13
14
20
26
41
76
103
381
0 100 200 300 400
NZL
NOR
FIN
DK
CH
ÖST
SE
H
BE
NL
AUS
CDN
UK
DE
USA
osteosarcoma incidenceca. 2-3 / mio/ year
ca. 50% eligible (approx. 730 /year)
EURAMOS-countries: max. recruitment / year
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EU-Clinical Trials Directive EC 2001/20
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Documentation to be held by investigator/ institution for clinical trials• Investigators brochure (+ updates) or SmPC• Protocol and amendments (signed)• Information sheet and consent form (+ updates)• Financial aspects• Insurance statements• Signed agreements between parties• EC opinion and composition• MRHA authorisation• Investigators CVs• Medical and laboratory tests, including normal ranges• Medicine labels• Instructions for medicine use• Shipping records• Certificates of analysis• Decoding procedures• Master randomisation list• Monitoring reports (pre-trial, initiation, close-out etc)• List of persons responsibilities delegated to (+ updates)• CRFs and corrections• SAE notifications from investigators and to EC and MRHA• EC/MRHA annual reports and final reports• Subject screening log• Subject identification code list• Subject enrolment log• IMP accountability at site• Record of retained tissues• Documentation of IMP destruction• Completed subject identification code list• Audit certificate• Clinical study report
Detailed guidance for the principles of GCP in the conduct in the EU of clinical trialson medicinal products for human use. ENTR/6416/01, July 2002
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EURAMOS Recruitment as of August 31, 2008EURAMOSEURAMOS Recruitment as of August 31, 2008
Thanks to EURAMOS-CDC, MRC London
1115 patientsfrom 281 institutions
in 15 countries
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EURAMOS Recruitment as of August 31, 2008EURAMOSEURAMOS Recruitment as of August 31, 2008
Courtesy of EURAMOS-CDC,
MRC London
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centers patients p/c
133 493 3.765 239 3.726 148 5.7
4 49 12.314 46 3.3
7 27 3.86 22 3.7
centers patients p/c
3 22 7.37 22 3.12 11 5.51 10 10.06 12 2.03 8 2.73 5 1.71 1 1.0
EURAMOSCountry-Specific Recruitment as of August 31, 2008
EURAMOSEURAMOSCountry-Specific Recruitment as of August 31, 2008
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0% 25% 50% 75% 100%
NZL
NOR
FIN
DK
CH
ÖST
SE
H
BE
NL
AUS
CDN
UK
DE
USA
EURAMOS-countries: Osteosarcomasnumber recruited vs. max. number possible (3.5 years)
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EURAMOSEURAMOS--1 / AOST 03311 / AOST 0331
• recruitment- surprisingly good- largest osteosarcoma study of all times in <3 years
• randomization- rate not quite as high as expected- room for improvement (???)
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Support of Participating CentersSupport of Participating Centers
• Monitoring
• Training
• Lobbying
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• Stuttgart, December 2005
• Oslo, October 2006
• London, January 2008
• Oslo, 2009
Training Courses
Supported by the
European Science Foundation (ESF)under the
EUROCORES Program European Clinical Trials (ECT), through contract No. ERASCT-2003-980409 of the European Commission, DG Research, FP6
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European Commission – EMEA Conference on the Operation of the Clinical Trials Directive (Directive
2001/20/EC) and Perspectives for the Future
3. October 2007, EMEA, London