Nordic Clinical
Trials and registries
in a pediatric
setting
Thomas Frandsen
Consultant, MD, PhD, Rigshospitalet
Copenhagen
May 23rd 2017
NOPHO
Cancer in children
Reasons for death in European ChildrenWolfe, Lancet 2013
NOPHO
Board
Leukemia
Committee
Working
groups
Database
Stockholm
Solid Tumor
Committee
Working
groups
Biobank
Uppsala
Working
groups
Scientific
Committee
CNS
Committee
Working
groups
Working
groups
Sweden and NOPHO registry
Made by Mats Heyman - CCEG
Nordic Cooperation
What is registered –
by Mats Heyman - CCEG
Nordic Cooperation
7 Countries, 7 languages
Population 30 millions
5 million children
200 ALL children per year
30 ALL treatment centres
Common NOPHO protocols
since 1986
Pediatric Cancer
Acute Lymphoblastic Leukemia
ALL
• Rare disesase
• Very little focus from the pharma
industry
• Central Database
• Biobank
Nordic Cooperation
Nordic Clinical Trial
Challenges
• 5 (7) countries, 5 (7) languages
• 5 (7) national authorities – Medicines
Agencies
• 5 (7)National Data protection agencies
• 5 (7) Ethical Boards
• 5 (7) interpretations of the EU Directive
and 5 (7) sets of ethical rules
• Strategy and funding for GCP
Nordic Cooperation
monitoring in Investigator Initiated trials
Incidence per 100,000 child years
ALL – mostly in children
10
NOPHO:
8
1986-1989
1990-1993
6
1994-1997
1998-2001
4
2
0
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Age (years)
Hjalgrim & Gustafsson et al (NOPHO) 2003
Event Free Survival for Childhood leukemia (ALL)
1,0
0,9
2002-2008
0,8
1992-2001
EFS survival
0,7
1986-91
0,6
1981-85
0,5
0,4
0,3
0,2
0,1
0,0
0
2
4
6
8
10
12
14
16
Years from diagnosis
18
20
22
24
26
NOPHO ALL-2008
Accrual goal (2008-2016):
1400 children
1.0-18 Years
300 children
1.0-18 Years
5 Nordic countries (+Rx)
2 Baltic countries (-Rx)
200 ADULTS 18-45 Years
DK, S, N, LT, EE (+F 2014) (-Rx)
Biobank
Database
For children and adults, identical:
Diagnostics (incl. cytogenetics)
Risc grouping
Common treatment
MRD-monitoring
Toxicity registration
Common platform for research
EE+
Study Centre
Nordic Cooperation
LT+
*
NOPHO ALL-2008 –
Nordic Investigator Initiated Trial
HR (10%)
A
B
C
A
B
C
A
B
C
IIC
R3
I-D+
IR (35%)
I-P+
R1
6MP 25 mg/m2
+/- dose increments
SR (55%)
0
4
5
IIC
IIDC
R2 PEGasp 1000 IU/m i.m. q2w or 6w
2
II
12 weeks
Nordic Cooperation
130
Children are not just small adults
Nordic Cooperation
Teenagers and young adults with ALL
Study
Year
N
EFS %
FRANCE
Child Dpt.
Adult Dpt.
1993-1999
1994-2000
77
100
67 (5y)
41
USA
Child Dpt
Adult Dpt.
1989-1995
1988-1998
196
103
64 (6y)
38
Child Dpt
1996-2003
1996-2003
150
92
78 (2y)
47
1985-1999
1985-1999
47
44
69 (5y)
34
1992-2000
1994-2000
1995-2000
144
50
49
65 (8y)
38
13
ITALY
Netherlands
NOPHO
Adult Dpt.
Child Dpt
Adult Dpt.
Child Dpt
Adults 15-25
Adults 25-40
Nordic Cooperation
*
Event free survival in Sweden
EFS
1,0
0,9
Probability
0,8
}
0,7
0,6
15-18 (P) 0.74
n=36
21-25
0.44
n=27
15-20 (A) 0.33
n=23
26-30
30-40
n=21
n=28
child
0,5
}
0,4
0,3
adults
0,2
0,1
0.18
0.11
0,0
0
2
4
6
8
10
12
Time from diagnosis (years)
Nordic Cooperation
From Hallböök & Heyman, Cancer 2006
P = pediatric procotol
A = adult protocol
Event Free Survival for Childhood leukemia (ALL)
NOPHO ALL 2008
NOPHO ALL 2000
NOPHO ALL 1992
DPS årsmøde 2012
Strategy for the trial
• Simple, on-line dataregistration,
including SAEs, Death and SUSAR’s
• Exclusion of known AE’s
• Continuous monitoring of entered data
by the study centre. Errors are picked up
within a short period.
• Nordic GCP network
• Help-desk
Nordic Cooperation
Strategy of monitoring
and registration
NOPHO ALL2008, children 1.0-17.9, pEFS March 2012
SR, 0.96
IR, 0.88
Event-free survival
HR+SCT, 0.72
HR, 0.66
Nordic Cooperation
Years from diagnosis
No SAE
Death
Any SAE
Other CNS
Osteonecrosis
Pancreatitis
Coma
Pres
Seizures
Vincristine Related
Hypertension
Heart Failure
VOD
Hyperlipidemia
Bleeding
Thrombosis
Liver Dys
Abdominal
Dialysis
Fungal infection
Pneumocystis
ICU
Allergy/Anaphylaxis
N=82
Total (n=699)
N=74
Total Quarterly
N=63
SAE’s
N=72
N=167
N=95
0
10
20
Nordic Cooperation
30
40
50
60
70
80
90
100
Total Quarterly
SAE’s Age divided
Nordic Cooperation
Strategy for the trial
• Simple, on-line dataregistration,
including SAEs
• Exclusion of known AE’s
• Continuous monitoring of registered data
by the study centre. Errors are picked up
within a short period.
• Nordic GCP network
• Help-desk
Nordic Cooperation
AEs not to be reported
•
a number of toxicities are so well-known and frequent during therapy that
they will not be reported. These includes:
•
For the 6MP increment study, the following will not be AE-reported:

 Since leukopenia is the target toxicity (monitoring parameter), this side-effect will not be
regarded as a SAE. This also includes febrile neutropenia leading to hospitalisation or prolongation
of ongoing hospitalisation if the patients condition otherwise is good with no signs of septic shock.
 Since thrombocytopenia is the target toxicity (monitoring parameter) this side-effect will not
be regarded as a SAE.
 A rise in aminotransferases with normal liver function tests (i.e. bilirubin and INR (or
coagulation factor 2-7-10) is a well-known side effect of HD-MTX and 6MP and will not be regarded
as a SAE, unless in combination with 19.3.1.8.
 A rise in bilirubin to less than 5x UNL.








 A fall in coagulation factors, unless in combination with 19.3.1.8.
 Less than a grade 4 rise in amylase (>5x UNL, if measured) will not be reported.
 Kidney dysfunction is a well-known side effect of HD-MTX and will not be regarded as
SAE unless it requires dialysis or leads to a permanent kidney dysfunction with s-creatinine >UNL.
 Stomatitis and dyspepsia with or without liver toxicity are a well-known side effects of
HD-MTX and will not be regarded as SAE.
 Infection/fever leading to hospitalisation or prolongation of existing hospitalisation.
Nordic Cooperation
Strategy for the trial
• Simple, on-line dataregistration,
including SAEs
• Exclusion of known AE’s
• E-CRF’s in same database
• Continuous monitoring of entered data
by the study centre. Errors are picked up
within a short period.
• Nordic GCP network
• Help-desk
Nordic Cooperation
Strategy for the trial
• Simple, on-line dataregistration,
including SAEs
• Exclusion of known AE’s
• E-CRF’s in same database
• Continuous monitoring of entered data
by the study centre. Errors are picked up
within a short period.
• Nordic GCP network
• Help-desk
Nordic Cooperation
Strategy for the trial
• Simple, on-line dataregistration,
including SAEs
• Exclusion of known AE’s
• E-CRF’s in same database
• Continuous monitoring of entered data
by the study centre. Errors are picked up
within a short period.
• Nordic GCP network
• Help-desk
Nordic Cooperation
Nordic Cooperation
Sponsor
Norway:
Coord. Investigator
Investigator
Investigator
Denmark:
Coord. Investigator
Investigator
Investigator
Sweden:
Coord. Investigator
Investigator
Investigator
Monitoring Plan
GCP-Unit
GCP-Unit
GCP-Unit
Strategy for the trial
• Simple, on-line dataregistration,
including SAEs
• Exclusion of known AE’s
• Continuous monitoring of data by the
study centre. Errors are picked up within
a short period.
• Nordic GCP network
• On-line Help-desk
Nordic Cooperation
Nordic Cooperation
Compliance
• Last registration period: 33 out of 34
centres registered (97%)(both adult and
child centers )
• >1200 patients with SAE registrations
per January 23rd – 2012
• > 99 % of eligible patients participate in
the common treatment protocol (2½ years)
• 85-90% participate in randomizations
Nordic Cooperation
Event-free survival
NOPHO ALL2008, Survival by age
1-9.9 years: N=448,
10-14.9 years: N=72,
15-17.9 years: N=54,
18-45 years: N=68,
pEFS 0.91
pEFS 0.76
pEFS 0.74
pEFS: 0.82
P=0.002
Nordic Cooperation
Years from diagnosis
Perhaps
adults are
just big
kids
Nordic Cooperation
Biggest challenge in the Nordic
Pediatric Oncology setting:
Ethical applications – not
registries
• One entry
Or perhaps
• VHP- like ethical application
Nordic Cooperation
Nordic Cooperation