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EORTC Protocol Review Committee (PRC)

Prior to activation, all protocols conducted by the EORTC require approval by an independent panel of experts. This independent peer review process was implemented by the EORTC in 1983. The Protocol Review Committee (PRC), appointed by the EORTC Board reviews all projects proposed by EORTC Groups.

For a study to be conducted under the EORTC label, EORTC experts must provide input into the study design and the protocol must to be approved by the PRC. In addition, the database should be handled by the Headquarters staff and the final analysis should be performed by an EORTC statistician unless conducted by another independent research group in the context of a so-called intergroup clinical trial.

The PRC is comprised of experts in the fields of cancer clinical research. All disciplines of oncology are represented in the review panel. About 30% of PRC members are non-EORTC which also includes a representation from the US National Cancer Institute (NCI). Additionally, the PRC makes systematic use of external reviewers – a minimum of three and a maximum of five international experts are consulted for each outline, thereby providing independent review.

The function of the EORTC PRC is to assess the compliance of studies proposed by the EORTC Groups with the EORTC scientific strategy, and to assess their scientific value in terms of originality, interest, methodology and scientific feasibility. The PRC assists the Groups whenever necessary concerning any aspect of the design and implementation of their studies from the first outline proposal to the full protocol.

Protocol outlines are submitted to the PRC secretariat via the Internet. Outlines are normally reviewed by e-mail. If necessary, they are discussed at PRC meetings; in such case, the study coordinator is invited to discuss, in person, the PRC concerns raised about his/her proposal during the meeting.

About 35% of submitted protocols are joint protocols with non-EORTC groups (e.g. GIMEMA, NCIC). The review of intergroup studies depends upon whether the EORTC is the coordinating group or joins a protocol which will be run by another data center.

Outlines may be approved at the time of review but more often are only approved after revision, while others are rejected. Most protocol outlines are resubmitted after detailed comments from the PRC, and can still at that time be reviewed by external experts from the particular field involved.

Outlines approved by the PRC may be subsequently developed as full protocols if the budget required to manage the study is fully covered. If this budget is not fully covered, they are subsequently submitted to a competitive selection process carried out by the EORTC Board. The Board decides to allocate EORTC funding (from the EORTC Academic Fund) on the basis of the scientific evaluation provided by the PRC. Selected projects are subsequently developed as full protocols. The “EORTC protocol submission, selection and development procedures” are described in the EORTC Policy 16, available on the EORTC website.

In order to simplify the writing of the full protocol, as well as to guarantee homogeneity of protocols and adherence to EORTC policies, the PRC in conjunction with the EORTC Protocol Help Desk have developed a set of core documents available to the EORTC Groups. The PRC approved documents include guidelines to improve the content/clarity of all protocols. Guidelines developed for the writing of each chapter, appendix of the protocol and standard versions for various administrative chapters are provided (i.e. insurance, ethical consideration, reporting of serious adverse events, randomisation).

All EORTC protocols are currently built in a modular fashion with logistical support from the EORTC Protocol Help Desk which assembles and edits each successive version of the protocol, follows the overall protocol development process and implementation of protocol amendments. The Protocol Help Desk assembles the final version of the protocol in the shortest possible time. Full protocols must be written in accordance with development outlines. Significant modifications of the study outline after its approval will require further approval again by the PRC. If the modifications impact the resources to be allocated by the EORTC, the decision of the EORTC Board to provide EORTC
support may be reconsidered.

All efforts are made to accelerate the review process to meet the demands of Groups to have protocols activated as quickly as possible but there is an absolute necessity for the PRC to assure that all studies with the EORTC label are conducted with the highest possible standards (scientific, administrative and regulatory) of clinical scientific investigation. The New Drug Advisory Committee (NDAC) and the Translational Research Advisory Committee (TRAC) provide additional scientific expertise when needed.

Members & Ex-Officio Members

Chairman: O. S. Nielsen, Aarhus (DK)
Vice-Chairman: J-Y. Blay, Lyon (FR)

J.-P. Armand, Toulouse (FR)
J. Bernier, Genolier (CH)
S. Bodis, Aarau (CH)
T. de Witte, Nijmegen (NL)
C. Dittrich, Vienna (AT)
F. Guillemin, Vandoeuvre les Nancy (FR)
E. Jäger, Frankfurt (DE)
C.-H. Köhne, Oldenburg (DE)
D. Lacombe, Brussels (BE)
F. Meunier, Brussels (BE)
J. Oliveira, Lisboa (PT)
M. Parmar, London (GB)
R. Rosell, Badalona (ES)
A. Sobrero, Genova (IT)
R. Sylvester, Brussels (BE)
M. van Glabbeke, Brussels (BE)
G. Velikova, Leeds (GB)
C. Weltens, Leuven (BE)

Phase I-II PRC Experts:
A. Awada, Brussels (BE)
J. Cassidy, Glasgow (GB)
M. De Jonge, Rotterdam (NL)
H. Dumez, Leuven (BE)
G. Eckhardt, Denver (US)
H.W. Hirte, Hamilton (CA)
I.R. Judson, London (GB)
P.J. O’Dwyer, Philadelphia (US)
A. Ravaud, Bordeaux (FR)
L. Seymour, Kingston (CA)
L. Siu, Toronto (CA)
J.-C. Soria, Villejuif (FR)
C. Takimoto, San Antonio (US)

PRC Review of outlines 2006 - 2007 (Sorted by date of first submission)

Study	Group(s)	Overall Strategy	Phase	outline submission	Final decision
26051	Brain Tumor	3A	III	14/03/2005	Accepted
40054 (1)	Gastrointestinal Tract Cancer	1A	III	07/11/2005	Accepted
10055 (2)	Breast Cancer	2A+	III	25/11/2005	Accepted
22055-08053 (2)	Radiation Oncology + Lung Cancer	2A+	III	05/12/2005	Accepted
26054	Brain Tumor	3B	I	05/12/2005	Accepted
24051	Head and Neck Cancer	3B+	I/II	07/12/2005	Accepted
10054	Breast Cancer	2B+	I/II	12/12/2005	Accepted
90051	NOCI	4	Epid. (3)	09/01/2006	Accepted
08061	Lung Cancer	2B	II	11/01/2006	Accepted
08062	Lung Cancer	3C	II	11/01/2006	Accepted
62061	Soft Tissue and Bone Sarcoma	3C	II	19/01/2006	Accepted
26061	Brain Tumor	3B+	II	23/01/2006	Accepted
26053-22054 (1)	Brain Tumor + Radiation Oncology	1A+	III	26/01/2006	Accepted
08063 (2)	Lung Cancer	2A+	III	31/01/2006	Accepted
30061	Genito-Urinary Tract Cancer	2B+	I/II	27/02/2006	Accepted
30062	Genito-Urinary Tract Cancer	3B+	II	28/02/2006	Rejected
08064	Lung Cancer	2B+	II	07/03/2006	Rejected
24061	Head and Neck Cancer	3C	II	04/04/2006	Accepted
24062	Head and Neck Cancer	3B	II	19/04/2006	Accepted
06061 (1)	Leukaemia	3B+	I/II	24/05/2006	Accepted
06062 (1)	Leukaemia	3B+	I/II	24/05/2006	Accepted
26062-22061 (2)	Brain Tumor + Radiation Oncology	2A+	III	09/06/2006	Accepted
90061	NOCI	3B	II	14/06/2006	Accepted
55061	Gynecological Cancer	3A+	II/III	02/08/2006	Accepted
90062	NOCI	4	Obs. (4)	10/10/2006	Cancelled
26063	Brain Tumor	3B+	II	23/11/2006	Accepted
62064-22064	Soft Tissue and Bone Sarcoma + Radiation Oncology	3A+	III	08/12/2006	Resubmit
62062	Soft Tissue and Bone Sarcoma	1A	III	08/12/2006	Resubmit
62063 (1)	Soft Tissue and Bone Sarcoma	1A	III	08/12/2006	Accepted
30063 (2)	Genito-Urinary Tract Cancer	2A+	III	22/12/2006	Accepted
18071	Melanoma	1A+	III	22/01/2007	Accepted
30071	Genito-Urinary Tract Cancer	3B	II	12/02/2007	Accepted
30072 (2)	Genito-Urinary Tract Cancer	3A+	II/III	12/02/2007	Accepted
10071 (2)	Breast Cancer	2A+	III	19/02/2007	Accepted
62071 (2)	Soft Tissue and Bone Sarcoma	1A+	III	06/03/2007	Resubmit
90071	NOCI	3B+	II	12/04/2007	Accepted
62072	Soft Tissue and Bone Sarcoma	1A	III	06/07/2007	Accepted
08072 (2)	Lung Cancer	1A+	III	06/12/2007	Pending

(1) Intergroup study coordinated by EORTC Groups
(2) Intergroup study to which EORTC Groups are collaborating
(3) Epidemiological study
(4) Observational study

Summary of the Protocol Review Committee activities 2006 - 2007

In the period beginning January 2006 to the end of December 2007 (refer to previous table), a total of 31 new outline proposals (3 Phase I-II, 12 Phase II, 2 Phase II-III, 12 Phase III, 1 epidemiological and 1 observational study) were submitted to the PRC. Of these, 24 were accepted, 2 were rejected and 1 cancelled. For one study, the review was still ongoing at the end of December 2007 and 3 outlines remain pending resubmission. Further to this, 7 outlines originally submitted in 2005 were accepted in 2006. The estimated median time for outline review was 42 days, ranging from 21 to 87 days. The upper values for this range include additional letter exchange with the Study Coordinator.

During 2006 and 2007, a total of 35 Full Protocols / Group Specific Appendices (GSAs) were submitted for review. Of those, 32 were approved; while 3 others were still in the review process at the end of 2007. The median time for reviewing a full protocol was 54 days and for examining a GSA, 7 days.

During the same period, 92 study amendments were approved (53 substantial and 39 non-substantial amendments).

Submission of outlines and protocols to the EORTC Protocol Review Committee

For each study proposed by an EORTC Group, an outline should be submitted to the EORTC. The outline should briefly describe and justify the principal parameters of the trial (objectives, principal eligibility criteria, therapeutic interventions, endpoints, statistical design, companion studies) in such a way that the PRC will be able to assess the scientific value of the proposed study. The outline should also identify a Study Coordinator appointed by the EORTC Group(s), and eventual non-EORTC partners.

All submitted outlines must be approved by the EORTC Group Chairman. Prior to PRC submission, the study concept will have been approved by the EORTC Executive Committee. EPOD (Early Project Optimization Department) will be in charge of the submission process.

Groups are encouraged to discuss their projects with EPOD prior to submission to the EORTC Executive Committee. EPOD provides support for and streamlines the EORTC Group projects and strategies ensuring that these are in line with the EORTC strategy as defined by the Board.

For studies that might contribute to a new drug development project, the Groups are advised to consult NDAC. For studies including a Translational Research project, the Groups are advised to consult TRAC. Eventual support of NDAC or TRAC should be notified at the time of outline submission.

The first PRC decision will be given to the EORTC Study Coordinator(s), the EORTC Group Chairman and the EORTC Headquarters team within one month of receipt of the outline (approval, resubmission or rejection).

Full Protocol Submission

Full protocols are developed in a modular way with the logistic support of the Headquarters Protocol Help Desk and the Headquarters team. Appropriate instructions, guidelines and templates will be addressed to the Study Coordinator by the protocol help desk shortly after outline approval.

When the final version of the full protocol is available, the Study Coordinator should send a submission letter (or e-mail) to the PRC secretariat, which includes an answer to all questions, comments and suggestions included in the outline decision letter, as well as the description of eventual differences between the accepted outline and the full protocol.

The final version will be submitted to an internal revision process within the Headquarters, to check adherence to the PRC-approved outline, compliance with EORTC Policies and with the EORTC Headquarters Standard Operating Procedures, and to detect eventual discrepancies or inconsistencies that may affect the conduct and/or the management of the study. In the case of major discrepancies with the original outline and/or unresolvable disagreement with the internal reviewers, the protocol will be resubmitted to the PRC experts.

All Study Coordinators are required to complete a conflict of interest form, according to the EORTC Conflict of Interest and Confidentiality Policy, and sign the document entitled “Tasks & Responsibilities of Study Coordinators”. Both documents are sent to the Study Coordinator at the time of outline approval and must be signed before submission of the full protocol.

Intergroup Studies
Intergroup studies should follow the EORTC Intergroup Policy. If the trial is coordinated by an EORTC Group or the EORTC Headquarters, the EORTC approval will be obtained through the usual submission procedure (see above). If the EORTC is neither the Coordinating Group, nor the Coordinating datacenter, the EORTC Group(s) should appoint an “EORTC Coordinator” who will complete an outline questionnaire (even if the full protocol is already available) and send the PRC secretariat a copy of all available documentation of prior project peer reviews (preferable as electronic documents). If the study is already active in another group, the reasons why the EORTC will join the trial at a late stage should be explained in the comment section of the outline questionnaire. If the full protocol is already finalised, it should be sent to the PRC secretariat at the time of outline submission (preferably as an electronic document). If the “EORTC Group Appendix” (see hereunder) is already finalised and approved by the EORTC Intergroup Office, the PRC Secretariat should be informed.

Development of the full protocol is normally the responsibility of the Coordinating Group. The EORTC Headquarters will develop an “EORTC Group Appendix”. The subsequent review process will be decided by the PRC on the basis of the information provided at the time of outline submission.

Amendments
After PRC approval, any modifications to the protocol must be discussed and subsequently sent to the Headquarters team that will appropriately submit or notify the PRC of the changes, implement changes to the protocol, and issue a new version. The Headquarters will appropriately circulate the amendment and the new version of the protocol to all investigators, and will inform health authorities and ethics committees when needed.

Practical Information
Outlines are submitted to the PRC secretariat via internet (by completing the outline submission questionnaire). Instructions are available on the EORTC website. For each new submission, an outline number and a password are automatically generated and communicated at the end of the submission process.

An EORTC study number will be allocated and added to the outline questionnaire by the PRC secretariat at the time of submission to the Executive Committee.

Submitted outlines may be modified (via internet, using the allocated password) until they are flagged as final. At that time, the Study Coordinator should send an e-mail to the PRC secretariat to confirm that the outline may enter the review process.

The PRC secretariat will ask for a “green light” from the Headquarters team and for a letter of support (or e-mail) from the Group Chairman before submitting the final version to the PRC. In the case of a project dealing with an investigational agent, the investigator brochure (and international publication(s) if applicable) must be sent, preferably in electronic format to the PRC Secretariat.

Development of the full protocol can only be initiated after approval of the outline by the PRC and selection of the project by the EORTC Board if EORTC funding is needed. Appropriate instructions will be sent to the Study Coordinator by the Protocol Help Desk shortly after approval.

Full protocols are assembled at the EORTC Headquarters by the Protocol Help Desk. Official submission should only be done when the final version is available; this only requires a submission letter (or e-mail) from the Study Coordinator.