1. Nordic Clinical Trials and registries in a pediatric setting Thomas Frandsen Consultant, MD, PhD, Rigshospitalet Copenhagen
May 23rd 2017

2. NOPHO

3. 3

4. Reasons for death in European Children
Cancer in children
Reasons for death in European Children
Wolfe, Lancet 2013

5. NOPHO Board Scientific Committee Leukemia Committee
Solid Tumor Committee
CNS Committee
Working groups
Working groups
Working groups
Working groups
Working groups
Database
Stockholm
Biobank
Uppsala

6. Sweden and NOPHO registry Made by Mats Heyman - CCEG
Nordic Cooperation

7. What is registered – by Mats Heyman - CCEG
Nordic Cooperation

8. Common NOPHO protocols since 1986
7 Countries, 7 languages
Population 30 millions
5 million children
200 ALL children per year
30 ALL treatment centres
Common NOPHO protocols since 1986 8

9. Pediatric Cancer Acute Lymphoblastic Leukemia ALL
Rare disesase
Very little focus from the pharma industry
Central Database
Biobank
Nordic Cooperation

10. 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 monitoring in Investigator Initiated trials
Nordic Cooperation

11. ALL – mostly in children
NOPHO:
Hjalgrim & Gustafsson et al (NOPHO) 2003

12. Event Free Survival for Childhood leukemia (ALL)
Years from diagnosis 26 24 22 20 18 16 14 12 10 8 6 4 2
EFS survival
1,0
0,9
0,8
0,7
0,6
0,5
0,4
0,3
0,2
0,1
0,0
Event Free Survival for Childhood leukemia (ALL)
Måling af

13. NOPHO ALL-2008 Biobank Database Study Centre EE+ LT+
Accrual goal ( ):
1400 children Years 5 Nordic countries (+Rx)
300 children Years 2 Baltic countries (-Rx)
200 ADULTS Years DK, S, N, LT, EE (+F 2014) (-Rx)
Study Centre
Database
Biobank
Riget
For children and adults, identical:
Diagnostics (incl. cytogenetics)
Risc grouping
Common treatment
MRD-monitoring
Toxicity registration
Common platform for research
EE+
LT+
Nordic Cooperation 13 13

14. NOPHO ALL-2008 – Nordic Investigator Initiated Trial*
NOPHO ALL-2008 – Nordic Investigator Initiated Trial R3
IIC
I-D+
I-P+
HR (10%)
IR (35%)
SR (55%) A B C A B C A B C
IIDC
IIC
6MP 25 mg/m2
+/- dose increments
PEGasp 1000 IU/m2 i.m. q2w or 6w R1 R2 II 4 5
12 weeks
130
Nordic Cooperation 14

15. Children are not just small adults
Nordic Cooperation

16. Teenagers and young adults with ALL
Study
Year N
EFS %
Child Dpt.
Adult Dpt. 77
100
67 (5y)
Child Dpt
196
103
64 (6y)
150 92
78 (2y) 47 44
69 (5y)
Adults
Adults
144 50 49
65 (8y)
FRANCE 41
USA 38
ITALY 47
Netherlands 34
NOPHO 38 13
Nordic Cooperation 16 16

17. Event free survival in Sweden*
EFS
1,0
0,9 }
0,8
15-18 (P) n=36
n=27
15-20 (A) 0.33 n=23
n=21
n=28
P = pediatric procotol
A = adult protocol
child
0,7
0,6 }
Probability
0,5
0,4
adults
0,3
0,2
0,1
0,0 2 4 6 8 10 12
Time from diagnosis (years)
Nordic Cooperation
From Hallböök & Heyman, Cancer 2006

18. Event Free Survival for Childhood leukemia (ALL)
NOPHO ALL 2008
NOPHO ALL 2000
NOPHO ALL 1992
DPS årsmøde 2012

19. 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

20. Strategy of monitoring and registration

21. NOPHO ALL2008, children 1.0-17.9, pEFS March 2012
SR, 0.96
IR, 0.88
HR+SCT, 0.72
HR, 0.66
Event-free survival
Nordic Cooperation
Years from diagnosis

22. Total Quarterly SAE’s N=82 N=74 N=63 N=72 N=167 N=95
Nordic Cooperation

23. Total Quarterly SAE’s Age divided
Nordic Cooperation

24. 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

25. 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 ) is a well-known side effect of HD-MTX and 6MP and will not be regarded as a SAE, unless in combination with
 A rise in bilirubin to less than 5x UNL.
 A fall in coagulation factors, unless in combination with
 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

26. 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

27. 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

28. 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

29. Nordic Cooperation Sponsor Norway: Coord. Investigator
Denmark: Coord. Investigator
Sweden: Coord. Investigator
Investigator
Monitoring Plan
GCP-Unit
GCP-Unit
GCP-Unit

30. 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

31. Nordic Cooperation

32. 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

33. NOPHO ALL2008, Survival by age
Event-free survival
1-9.9 years: N=448, pEFS 0.91
years: N=72, pEFS 0.76
years: N=54, pEFS 0.74
18-45 years: N=68, pEFS: 0.82
P=0.002
Nordic Cooperation
Years from diagnosis

34. Perhaps adults are just big kids
Nordic Cooperation

35. Biggest challenge in the Nordic Pediatric Oncology setting: Ethical applications – not registries
One entry
Or perhaps
VHP- like ethical application
Nordic Cooperation

36. Nordic Cooperation