EuroNet- PHL- C2 trial set- up and trial monitoring

Transcription

1 EuroNet- PHL- C2 trial set- up and trial monitoring Chris9ne Mauz- Körholz Department of Pediatrics Pediatric Hematology and Oncology UKGM, Justus- Liebig University of Gießen, Germany ScienCfic Secretary of the EuroNet- PHL group 1

2 Presenta)on Topics EuroNet- PHL Group Organisa(on Sponsor`s Overview brief review of the protocol Risk analysis of EuroNet- PHL- C2 Monitoring Plan ü Organisa(on of Monitoring ü Responsibili(es of the Na(onal Chairperson ü On- site monitoring ü Central monitoring ü Biometrical monitoring 2

3 Presenta)on Topics EuroNet- PHL Group Organisa(on Sponsor`s Overview brief review of the protocol Risk analysis of EuroNet- PHL- C2 Monitoring Plan ü Organisa(on of Monitoring ü Responsibili(es of the Na(onal Chairperson ü On- site monitoring ü Central monitoring ü Biometrical monitoring 3

4 EuroNet- PHL Organisa)on European Network for Pediatric Hodgkin Lymphoma Pediatric Hodgkin Lymphoma study groups (Europe, Israel, ANZCHOG) General Assembly of the EuroNet- PHL members Na(onal chairpersons Inves(gators and site staff Coopera(ng specialists (pathology, biology, imaging radiooncology) Clinical Board of EuroNet- PHL Representa(ves of the 6 largest countries/high- recruiters 2 representa(ves for the other countries (rota(ng) Biometrician, Imaging Specialist, Radio- Oncologist, Scien(fic Secretary DMSC for the respeccve trials 4

5 EuroNet- PHL- par)cipa)ng sites 5 EuroNet- PHL- current and future management 5

6 Presenta)on Topics EuroNet- PHL Group Organisa(on Sponsor`s Overview brief review of the protocol Risk analysis of EuroNet- PHL- C2 Monitoring Plan ü Organisa(on of Monitoring ü Responsibili(es of the Na(onal Chairperson ü On- site monitoring ü Central monitoring ü Biometrical monitoring 6

7 EuroNet- PHL Sponsor`s Overview Sponsor Justus Liebig University Coordina)ng Chairperson ZKS- L Datamanagement On- Site Monitoring (GER) Sta(s(cal Monitoring Na)onal Chairperson / Coopera)ng Ins)tu)on ZKS- M Sponsor Audits Na(onal Trial Organisa(on Subcontracts with local sites/ PIs 7

8 Presenta)on Topics EuroNet- PHL Group Organisa(on Sponsor`s Overview brief review of the protocol Risk analysis of EuroNet- PHL- C2 Monitoring Plan ü Organisa(on of Monitoring ü Responsibili(es of the Na(onal Chairperson ü On- site monitoring ü Central monitoring ü Biometrical monitoring 8

9 EuroNet- PHL- C2 trial design NORM- mee(ng Copenhagen

10 EuroNet- PHL- C2 trial design (TL- 1) NORM- mee(ng 10 Copenhagen 2018

11 EuroNet- PHL- C2 trial design (TL- 2/3) 11

12 Study Design in TL Two study ques)ons 2 OEPA ERA AR R IR ERA 2-4 COPDAC-28 vs. 2-4 DECOPDAC COPDAC-28 vs. 2-4 DECOPDAC-21 LRA DECOPDAC-21 better? RT-IF 20GY + Boost LRA+ RT 30GY to LRA+ only DECOPDAC-21 + limited RT non-inferior? 12

13 Actual accrual 13

14 Reference Pathology 14

15 Presenta)on Topics EuroNet- PHL Group Organisa(on Sponsor`s Overview brief review of the protocol Risk analysis of EuroNet- PHL- C2 Monitoring Plan ü Organisa(on of Monitoring ü Responsibili(es of the Na(onal Chairperson ü On- site monitoring ü Central monitoring ü Biometrical monitoring 15

16 Risk Analysis Monitoring in EuroNet- PHL- C2 follows a risk- based approach. The objec(ve is to achieve high protocol compliance and data quality, as well as to ensure pa(ents safety and rights. Central clinical and biometrical monitoring procedures will be combined with on- site monitoring visits to op(mise efficacy. 16

17 Risk Analysis Quality endpoints have been defined in the study protocol. Treatment delivery parameters, toxici(es, (ming of imaging, follow- up informa(on and informed consent documents comprise risk- bearing trial aspects which have to be supervised. All images for staging and response assessment are submided to real Cme central review. Protocol devia(ons par(cularly in (ming will be reliably and promptly detected in the central review resp. central monitoring process and respec(ve feedback provided. 17

18 Risk Analysis The radiotherapy quality control team will check quality of radiotherapy applica(on and they will provide training for radio- oncologists in case of severe devia(ons in radiotherapy applica(on. OEPA and COPDAC- 28 chemotherapy are standard treatments with well- known toxicity profiles. DECOPDAC- 21 is a new treatment component. Thus monitoring of safety and treatment delivery will focus on DECOPDAC- 21 in direct comparison with COPDAC- 28 consolida(on in TL- 2 and TL

19 Risk Analysis All trial drugs in EuroNet- PHL- C2 are part of standard care. Therefore, there are no special requirements regarding transport, storage, dispensing, return, destruc(on of inves(ga(onal products, and drug accountability. Biometrical monitoring will be performed. Thus, many issues related to pa(ent`s safety are covered by central monitoring On- site monitoring will focus on original pacent s safety data, aspects of protocol compliance and key data outside the scope of the above central supervising processes. 19

20 Presenta)on Topics EuroNet- PHL Group Organisa(on Sponsor`s Overview brief review of the protocol Risk analysis of EuroNet- PHL- C2 Monitoring Plan ü Organisa(on of Monitoring ü Responsibili(es of the Na(onal Chairperson ü On- site monitoring ü Central monitoring ü Biometrical monitoring 20

21 21

22 Monitoring Flow Chart 22

23 Resonsibili)es of the Na)onal Chairperson The Na(onal Chairperson is responsible for trial conduct in the respec(ve country including monitoring. The Na(onal Chairperson reports annually to the Coordina9ng Chairperson on conduct of monitoring, since the Coordina(ng chairperson will be supervised by the Sponsor`s quality assurance unit. u Agreement with Sponsor incl. Delega(on of Sponsor du(es u Training by Coordina(ng Chairperson u Sub- Contracts with Na(onal Trial Sites u Appointment of Clinical Monitors u Supervision of Na(onal Monitoring 23

24 On- site monitoring Key data checks Informed consent The informed consent documents will be checked for Existence and completeness of the age- specific document set Correct version Pa(ent s name and/or pa(ent ID clearly iden(fiable Complete and correct signatures (age specific as required by the na(onal law, all person(s) having the care and custody of the child acc. to na(onal law) Document dated by pa(ent resp. person(s) having the care and custody of the child Acceptance/refusal of forwarding of real names (Central Review) Acceptance/refusal of randomisa(on (if appl. acc. to na(onal law) Inclusion/Exclusion criteria Only the following eligibility criteria will be checked Histologically confirmed primary diagnosis of classical Hodgkin s lymphoma Check: If CD20+, reference histology must be obtained before start of treatment (differen(al diagnosis to nodular lymphocyte predominant HL) Exclusion of pregnancy in girls of childbearing poten(al Check: Has a pregnancy test been performed prior to inclusion 24

25 On- site monitoring Serious Adverse Events (SAEs) For SAEs already reported, the following informa(on will be verified using pa(ent s source data: Presence of SAE- CRF as copy in the ISF (the original has to be sent to Central Study Office) If the hardcopy of a reported SAE is missing in the ISF, the CRA has to arrange a copy of SAE report is sent by the Central Study Office Pharmacovigilance to the trial Pa(ent- ID Descrip(on of the event Start/End dates Documenta(on of Chemotherapy Agents Inves(gator s signature Compliance with repor(ng according to protocol (Date of no(ce) Compliance with repor(ng deadlines to Competent Authori(es (legwork by Central Study Office) Queries related to the SAE (legwork by Central Study Office) AE/SAE- Reconcilia(on in case of discrepancies (legwork by Central Study Office) Baseline assessments 25

26 On- site monitoring Chemotherapy delivery The following aspects of treatment delivery will be checked (taking the biometrical monitoring synopsis into account): Whether chemotherapy doses follow protocol in DECOPDAC/COPDAC cycles in TL Whether dose modifica(ons or delays (no(ced on- site or detected in biometrical monitoring) are medically jus(fied. Prednisone/prednisolone tapering (not allowed in the protocol) in chemotherapy cycles immediately preceding response assessment with PET. Toxicity Toxici(es correctly documented (focus on DECOPDAC/COPDAC in TL- 2+3) All acute toxici(es documented correctly? Efficacy The following aspects will be checked Pa(ents with delay of more than one year in follow- up Inves)gator Site File (ISF) review 26

27 Frequency of On- site monitoring Frequency of monitoring visits The first visit of a trial site is scheduled axer end of chemotherapy for the first randomised TL- 2 or TL- 3 pa)ent. Further frequency and extent of monitoring depend on the accrual rate, on the results of the previous monitoring visit and on findings in central or sta)s)cal monitoring. Ac(ve trial sites without relevant findings on the last monitoring visit will be visited amer accrual of ten new pa)ents, but at least axer two years if at least two new pa)ents were randomised. Ac(ve trial sites with relevant findings during the last monitoring visit will be visited amer accrual of five new pa)ents, but at least axer one year if at least two new pa)ents were randomised. 27

28 Frequency of On- site monitoring Extraordinary for cause visits may be scheduled if required due to par(cular problems. Addi(onal visits axer stop of accrual may be scheduled to deal with urgent queries or delays in follow up documenta(on. Close- out visits are not planned. Relevant documents to be archived by Sponsor will be requested by Central Study Office. 28

29 Central Monitoring Hodgkin Study Office - Gießen (PedHemOnc) Pa(ent Registra(on (pseudonymized to Leipzigà DB) Central Review Board Staging and Response Assessment Pharmacovigilance Hodgkin Study Office - Leipzig (ZKS) Central Database Query Management SAE- Database, Pharmacovigilance Biometrical Monitoring 29

30 TeleHERMES IT Security, Data Protection No transfer of data from server to local PCs Transfer of Encrypted Data (https, using port 443) Individual Hospital log in and pw for sending studies option of anonymization Global TeleHERMES Server Audit trail of server activity Review board members Individual log in and pw to access data and application EuroNet- PHL- current and future management 30

31 Sta)s)cal/biometrical monitoring Hodgkin Study Biometrician - Leipzig (ZKS) Regular sta(s(cal reports distributed to Coordina(ng Chairperson, Clinical Board, and/or to DMSC on request (if applicable) Circulated to Na(onal Chairpersons 31

32 Registra)on and assignment to TL 32

33 Follow- Up 33

34 Event- Free- Survival 34

35 EuroNet- PHL- C2 Audits 35

36 Conclusions Excellent accrual Excellent randomiza(on rate Actual results are on target Toxicity in the DECOPDAC arm is tolerable 36

37 Acknowledgement Thank you! To all site staff (inves(gators, nurses, documentalists), pa(ents and families for par(cipa(on in the trial Thank you! To the Deutsche Krebshilfe for trial funding 37