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The European Network of Gynaecological Oncological Trial Groups (ENGOT) is a research network of the European Society of Gynaecological Oncology (ESGO), which was founded in 2007. Currently, 21 European trial groups are members of ENGOT (Appendix). As a network of European national or regional clinical trials groups, ENGOT has successfully conducted more than 70 European clinical trials in gynecological malignancies. The majority of clinical studies performed via the ENGOT are randomized Phase III trials, which have led to drug approvals and changes in the standard of care in gynecological malignancies. At a meeting in 2013, the ENGOT Strategic Group decided to initiate working groups for early drug development, biobanking, translational research, and rare gynecological cancer. Within the Horizon 2020 plan, a European Cooperation in Science and Technology (COST) action was proposed by ENGOT and financed with the goal of promoting networking in the field of rare gynecological cancer. This action was named Gynocare (https://www.cost.eu/actions/CA18117/%23tabs%7CName:overview).
The goal of all these ENGOT working groups is to accelerate the development of new therapies, based on a solid scientific rationale, for women with gynecological cancer through European collaboration, from concept to cure. For this purpose, we use the multidisciplinary expertise available within ENGOT and promote networking among expert centers belonging to different European countries. ENGOT also collaborates with groups outside the European Network.1 To achieve this goal, collaboration with industry partners is essential to quickly translate innovation into improved patient care.
The ENGOT groups’ “Requirements for Trials between Academic Groups and Industry Partners” was published in the International Journal of Gynecologic Cancer in 2010.2 These were re-evaluated and published in 2015 with the experience gained following the performance of several large randomized phase III trials.3 In these prior manuscripts, three Models of cooperation (Models A, B, and C) are described, which have been successfully implemented during cooperation with industry partners and when developing hypothesis generating and practice changing phase II and phase III clinical trials. However, the model of cooperation with industry now needs to be extended and adapted due to the complexity of the new research programs that are required to achieve the goals mentioned above.
Based on this premise, we herein propose an additional model of cooperation with industry, Model D, that will help to establish more efficient ways of developing clinical trials in the evolving landscape of gynecological cancer.
A number of situations require a new ENGOT Model D:
The development of new types of clinical trial design such as
umbrella and basket trials in which different drugs/medical devices from different industry partners are tested in multiple arms as single agents or in drug combinations in one or more clinical indications.
biomarker/pathway-driven trials in different tumor types with different drugs/medical devices from various industry partners tested over time within an adaptive model
The need for a more integrated framework to allow multi-industry cooperation with multiple academic groups within ENGOT within the same platform and if necessary with other groups outside ENGOT
The desire to create the opportunity to develop different drugs/medical devices over time within one platform to increase speed of development.
The objective of this manuscript is to describe the new Model D which incorporates the previous models and offers an opportunity for closer collaboration among multiple industry partners and multiple academic groups in early drug/medical device development.
This manuscript was discussed and approved by working group 4 (dedicated to bridging the gap between industry and biotechnology companies and translational research projects) and Action Chair of the Gynocare project and by the ENGOT Early Drug Development Network. It also underwent approval by the ENGOT Strategic Group and the ENGOT General Assembly prior to publication.
Description of Model D
Model D allows the performance of several Phase I/II clinical trials with one or more industry partners and multiple ENGOT groups within an integrated program.
In the following, we will refer to a program as a research concept that requires Model D cooperation for early drug/medical device development (Figure 1).
Examples for programs according to Model D. Cooperations between A) one industry partner and multiple ENGOT academic groups, and B) several industry partners and multiple ENGOT academic groups are depicted. In A) the example of specific contracts between the industry partner and each academic group is depicted. Alternatively, one master contract between the industry partner and one academic group can be executed and an additional intergroup agreement can be established among all participating academic groups in the program. In case of cooperation with other groups outside ENGOT within a program one or more clinical trials can, for example, be led by these other groups. The rules for ENGOT collaboration with other groups have been published previously,1 MoU: Memorandum of understanding.
When implementing Model D, a Memorandum of understanding (MoU) will be signed between industry partner(s) and ENGOT with the sole goal of documenting the willingness of cooperation on a specific program. The legal framework will subsequently be included in the contracts of the specific trials between industry and the respective lead ENGOT group of each trial. The signed MoU will require a formal amendment if an additional industry partner wishes to be included and to contribute to the program. The residing ENGOT chair at the time of document completion will sign the MoU.
This MoU will specify in detail the following:
introduction with the aims of the program
description of the unmet need in the area of the actual program with details of underlying reasons that require cooperation within the new Model D
definition of further procedures needed to implement the final program and describe the governance and timeline of the program
description of the cooperation: the program may involve multiple industry partners and multiple ENGOT academic groups
definition of the intellectual property rights
description of the clinical setting and the clinical trials within the program
maintenance of confidentiality
Once the MoU is signed, each clinical trial of the program under the MoU will require separate contracts between the industry partner and the involved lead ENGOT group detailing all aspects including the roles and responsibilities. An alternative option is to execute one master contract between the industry partner and one ENGOT group and to additionally establish an intergroup agreements among all involved cooperating ENGOT groups.
These contracts will follow one of the previously described ENGOT Models.2–4 In the case of trials involving drugs/medical devices from different industry partners, contracts between industries may be needed.
Database property and intellectual property
The sponsor of each clinical trial has the ownership of the data within that trial.
The sponsor can be an academic or cooperative group member (Model A or B) or an industry partner (Model C). In Model A, the database resides with, and is owned by the Lead ENGOT Group. In Model B, the database resides at a contract research organization (CRO) but is owned by the Lead ENGOT Group (who is also the sponsor). In Model C, the database resides at a CRO, and the CRO is contracted by the industry partner (sponsor) or alternatively the database resides at the industry partner. The choice of a CRO is made in mutual agreement between ENGOT and the industry partner (where possible).
With respect to study drug/medical device inventions, the right to commercially develop the drug/medical device-related results of a trial remains the property of the industry partner both in industry and academically sponsored trials (as per contractual terms).
In the case of more than one industry partner being involved in the same clinical trial, each industry partner retains the intellectual property (IP) of their own drug/medical device.
In the case of academically sponsored trials, the industry partner and the academic sponsor will negotiate a financial allocation for the complete transfer of the data for commercial purposes or filing at the timepoint of available results (as applicable). This procedure of negotiation will be part of the contract. The information regarding potential commercial use of the data will be included in the informed consent form (ICF).
Biomarker inventions related to the use of the study drug/medical device generated by the academic groups will be negotiated in the contract. All inventions not related to the use of the specific study drug/medical device and generated by the academic study groups may be the property of the academic groups in both academically and industry sponsored trials (eg, translation research findings that might be patentable). Any shared IP arising from the program will be negotiated in the contract.
Essential documents of Model D
For each program, a template protocol, a template ICF for clinical trial participation and for sample acquisitions, a template eCRF (with common database elements) and (if applicable in industry-sponsored trial) a template translational sub-study protocol lead by the ENGOT group with respective ICF, will be developed. The template protocol will include mandatory elements that are shared among the specific clinical trials within the program (eg, rationale of the program, rationale of intervention, minimum set of in-/exclusion criteria, description of bio sampling, common statistical plan and endpoints, etc) and also adaptive elements. The mandatory elements of the template protocol must not be modified in the specific clinical trial protocol within the program while the adaptive elements can be specific to each distinct clinical trial.
Common clauses will be developed that should preferably be used in the contracts between industry partner(s) and ENGOT academic group(s) for each clinical trial in the program. Ideally a master contract can be drafted for each program.
Principles of Model D programs
Timelines are of particular importance in early drug/medical device development with adaptability and flexibility being key enablers to speed. Model D programs allow a high rate of adaptability, for example, by quickly adding a cohort (specific trial) into a basket trial program if sufficient data emerge to support expansion or by adding a new drug/medical device (specific trial) if new evidence supports its use in a particular patient population. ENGOT aims to build in high flexibility into Model D programs to allow emerging data to be taken into consideration.
Besides increased implementation of these key elements for early drug/medical device testing in Model D programs, a major strength of ENGOT is efficacy in recruitment via the national academic groups. ENGOT has simultaneously conducted multiple randomized Phase III trials in similar indications by providing a large number of sites and avoiding overlapping trials at academic sites. A high number of experienced Phase I/II centers were identified within the ENGOT academic groups (ENGOT Early Drug Development Network). The organization of early drug/medical device development via academic groups will allow avoidance of overlap at clinical sites in trials involving the same patient population within a program, and will be particularly beneficial in Model D programs involving multiple industry partners allowing allocation of different clinical sites to distinct trials. Furthermore, the organization of ENGOT via academic groups has proven capability to successfully run clinical trials in rare gynecological cancers.
Besides, ENGOT trials are based on scientific soundness and rigor, highest data quality, and quality execution of trials according to Good Clinical Practice.
Translational platform and biobanking
Programs performed according to Model D have a priority to promote translational research and biomarker discovery particularly in early drug development and rare gynecological cancer. The translational activity does not have to be limited to the actual mechanism of action of the specific drug but should contribute to the better understanding of the disease. For biobanking, the use of the ENGOT biobank is strongly recommended and should be negotiated in the contract.
For industry sponsored clinical trials, a parallel academically led biobank together with a joint translational research plan should be considered. If this is not an option in an industry sponsored trial, a translational sub-study protocol, sponsored by an academic ENGOT group, and respective ICF can be developed. ENGOT academic groups should have priority in accessing residual biosamples held by industry partners in order to perform academic research. The ICF and contracts should include this possibility.
In the case of an academically sponsored trial, the biosamples will be collected, stored, and managed under the responsibility of the ENGOT lead group. Any research project on collected biomaterials that is not pre-defined must be approved by the Scientific Board of the program and conducted according to the national regulations of the patient-enrolling countries in the program.
Statistical considerations
Within the program one common statistical analysis plan (SAP) should be considered and it is preferable to have at least one academic statistician involved. In addition, in each clinical trial within the program, a second academic statistician may be involved. The entire database of the program should be made available for later meta-analyzes or subgroup analyzes by the academic group or an intergroup consortium after approval of sponsor and the Program Scientific Board.2
Committees
Each program will appoint a Program Scientific Board that will be responsible for:
coordination and harmonization of the different clinical trials in the program
approving the template protocol, template eCRF, template ICFs, SAPs, and common clauses of contracts
checking implementation of common elements of essential documents in each clinical trial
approving each clinical trial protocol
approving the publication plan arising from the overall results and sub-studies of the program (distinct from results of each clinical trial)
proposing and/or evaluating the need to amend the MoU
The Program Scientific Board will appoint a Chair. The Program Scientific Board will include at least one operational person and, if needed, experts in the development and implementation of translational research or other relevant areas. Additional subcommittees (eg, Molecular Diagnostic Committee) can be appointed by the Program’s Scientific Board, if needed. In Model D programs consisting of Model C trials, the Program Scientific Board will also have representatives of industry partner(s).
Each clinical trial within the program will appoint its own trial Steering Committee according to the general ENGOT rules. Responsibilities of the ENGOT Trial Steering Committee members are described earlier.2 4 The Chair of each trial Steering Committee will be a member of the Program’s Scientific Board.
Publication rules
Model D will in general follow the rules for ENGOT publication (https://engot.esgo.org/discover/for-partners/).
In the case of a phase I/II trial within the program that has a substantial translational research component, separate rules compared with the general ENGOT publication rules (as pointed out above) apply when a manuscript is primarily concerned with the results of combined clinical endpoint (eg, progression-free survival) and a translational research endpoint. This might make it necessary to include authors not primarily affiliated to a group but contributing to laboratory work. In this case, rules must be agreed on in advance and presented to ENGOT at the time point when the group applies for an ENGOT trial number.
The recommendation for defining authorship rules prospectively applies in particular for research projects in which the principal investigator of the clinical trial may neither get the first nor the senior position.
Overall, the publication authorship should consider both the groups’ contribution and translational laboratory activities. A minimum 51% of authorship positions should be distributed by the groups and reflect the general ENGOT publication rules.
Acknowledgments
We acknowledge the contribution of the Pacesetter Clinical Research Group and the following industry partners by reviewing this manuscript and providing valuable comments (in alphabetic order): AstraZeneca, Clovis Oncology, Eisai, Genmab, Merck/MSD, Novocure, and Roche
Footnotes
Collaborators European Network of Gynaecological Oncological Trial Groups (ENGOT)
Contributors All authors were actively involved in the development of the new Model D of cooperation between ENGOT and industry partners and in writing of the manuscript. This process involved two physical meetings, teleconferences, and email communication. All authors agreed to be accountable for all aspects of the work and approved the manuscript for submission.
Funding This document is part of the “Gynocare” action, financed by The European Cooperation in Science and Technology (COST), grant action Ca18117.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; internally peer reviewed.