Trials Portfolio

KEY AIMS OF AN INTEGRATED SYSTEM COMPREHENSIVE PEER-REVIEW SYSTEM FOR CANCER CLINICAL TRIALS IN THE UK THE COMPOSITION OF CTAAC ASSESSMENT OF PROPOSALS ADMINISTRATION INFORMATION PACK AND OUTLINE PROPOSAL STAGE FULL PROPOSALS SOURCES OF APPLICATIONS TO CTAAC REVIEW OF THE NEW ARRANGEMENTS MRC/CRUK JOINT FUNDING MECHANISM

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1. KEY AIMS OF AN INTEGRATED SYSTEM

1.1	With the advent of the National Cancer Research Institute (NCRI) and the National Cancer Research Network (NCRN) an opportunity exists to greatly improve the cancer clinical trials base in the UK. Key targets are to double recruitment and develop a balanced ‘national portfolio’ of cancer trials. These aims are shared by NCRI Partner organisations and embraced by the clinical research community.
1.2	A key step in reaching these targets is the provision of new infrastructure and network management through the NCRN. Equally important is an evolution of the peer-review and funding mechanisms operated by NCRI partners to provide a clear, streamlined system that provides quality peer-review, in an appropriate way, for a range of different size and types of trial.
1.3	Cancer Research UK, LRF and MRC, in consultation with a number of interested parties, including the NCRN Steering Group have been working on a proposed way forward that will work for a range of different types of trial. There is general agreement that any system will need to evolve and incorporate regular feedback from the research community. Feedback from key stakeholders will be encouraged and the process can then be adapted over time to meet the needs of the investigators, funding bodies, NCRN and consumers.
1.4	The principle requirements of an effective review and funding process are seen as: Clarity for the research community Quality standards Rapid decision making Transparency and independence Relevance for the UK’s cancer trials portfolio

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2. COMPREHENSIVE PEER-REVIEW SYSTEM FOR CANCER CLINICAL TRIALS IN THE UK

2.1	There is general agreement that the rigor, and thus the speed, of peer-review and consultation processes should reflect the complexity of the study and the degree of financial risk it represents. For example, large-scale screening trials often need a degree of discussion and peer review in keeping with their complexity and the number of stakeholders involved. Smaller therapeutic or diagnostic trials can be reviewed using a more responsive streamlined approach, commensurate with the level of complexity and financial risk, providing appropriate quality standards are met. A co-ordinated system is therefore proposed with two channels, one that handles small and medium-sized therapeutic and diagnostic trials and one designed for national screening studies and, where appropriate , very large therapeutic trials.
2.2	A new Committee CTAAC (Cancer Trials Awards and Advisory Committee) has been established. It will be responsible for reviewing and funding the majority of academic cancer trials in the UK. CTAAC will principally review phase III trials but will also consider phase II trials of licensed compounds in new indications. Feasibility studies of new treatment schedules may also be eligible. It is expected that, if the feasibility study were successful, a phase III trial would be developed and submitted to CTAAC. Established mechanisms for supporting Phase I/II trials and the development of new therapeutic agents already exists and CTAAC will not replicate these.
2.3	CTAAC will have a budget that will consist of the existing budget for the CRUK Clinical Trials Committee and a new contribution from the MRC. Given the likely budgetary constraints, it is anticipated that applications to CTAAC will be for a maximum of £100k per annum. Outlines for more expensive trials will be considered by CTAAC and, if approved, can be submitted as full proposals to the MRC. Continuity will be ensured by overlapping the membership of CTAAC and the MRC Research Boards (see 3.2). The review process for these large trials may be more extensive, and therefore slower, but, given the size and complexity of such studies and the degree of financial risk involved, this is felt to be acceptable. Whilst the MRC will take the lead in processing this type of application, the other funding bodies may consider co-funding such trials. An overview of the scheme is presented in the attached figure.

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3. THE COMPOSITION OF CTAAC

3.1	Membership of CTAAC will be jointly agreed by MRC and CRUK. The Chair will be a distinguished, independent, non-oncologist. A Co-Chairman, who is an oncologist, will also be appointed. CTAAC will be composed of 18-20 individuals, the majority of whom will comprise UK academic cancer specialists with a broad understanding of cancer research and clinical trials. In addition, experts from other trials related disciplines (eg Statistics, health economics, public health, quality of life, translational research) will be involved as appropriate and may be invited to join the Committee on an ad hoc basis. It is not intended that there will be representatives from each of the various NCRI Clinical Studies Groups.
3.2	Initial membership of CTAAC will be partially drawn from existing members of CTC and OTAC who will provide some stability for review of ongoing applications. There will also be cross membership with the CRUK’s Scientific Committee and MRC Research Boards. Membership will be for a maximum of three years (with the option of a one year extension).
3.3	The goal is to have a membership in which the combined knowledge of the group spans the diversity of applications. In practice this is difficult to achieve and CTAAC may be supplemented by ad hoc membership and written opinions to support the review of particular applications.
3.4	An International Panel of 8-12 experts, the International CTAAC Advisory Panel (ICAP), will be convened to review applications at the outline stage. Panel comments will be based on a structured set of criteria on which each application will be judged. ICAP’s comments will inform CTAAC’s view on the quality and international competitiveness of the proposal and assist in providing feedback to the applicants.
3.5	CTAAC will include observers from the NCRN Coordinating Centre to ensure the NCRN is aware of portfolio developments of relevance to the NCRI Clinical Studies Groups and NCRN Research Networks.

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4. ASSESSMENT OF PROPOSALS

4.1	The scope of CTAAC’s responsibilities lies in two key areas: to assess the scientific and technical merit of an application, and to comment on other aspects of the application which should be clearly separated from the assessment of scientific merit. This might include, likelihood the trial could change clinical practice, relevance to the UK trials portfolio, impact on the NHS etc.
4.2	Assessment criteria are as follows: Clinical importance of the research question Scientific importance of the research question Adequacy of background and preliminary data Strength of study design, including statistical design Expected interest/appeal to patients and likelihood of adequate accrual Anticipated opening for trial in portfolio

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5. ADMINISTRATION

5.1

The secretariat for CTAAC will be initially based at the CRUK. CRUK officers will take the lead in administration of all outline applications and full proposals to CTAAC. The MRC will assist in this process (identification of referees etc.). MRC Officers will take the lead in reviewing full applications which are likely to be beyond CTAAC’s budget.

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6. INFORMATION PACK AND OUTLINE PROPOSAL STAGE

6.1	The information pack is available electronically. This provides clear instructions on how to submit an application and also provides details of the criteria by which trials will be reviewed and scored.
6.2	Full contact details of CTAAC officers are provided and applicants will be encouraged to discuss their outline proposal prior to submission.
6.3	CTAAC will meet three times each year to review applications. Applications may be submitted throughout the year and deadlines for meetings will be posted on the web. Any application missing a deadline will be reviewed at the next meeting.
6.4	Outline applications will first be reviewed electronically by the International Panel. NCRI Clinical Studies Groups will be asked to comment on the relevance of the proposal to the national portfolio and the feasibility of recruitment targets, particularly in the light of any competing trials. Comments from both of the above will inform CTAAC’s subsequent discussions.
6.5	Following the meeting of CTAAC the secretariat will produce a record of the discussion using a template based on the criteria detailed above. This will be used to provide feedback to applicants and inform consideration of the full proposal.
6.6	Outlines will either be invited or declined. In exceptional circumstances applicants may be invited to resubmit an outline following substantial revision. Feedback will be provided to applicants where outlines are declined but revision and resubmission of these proposals will not be encouraged.
6.7	Applicants who submit outlines which are taken forward by MRC will receive feedback in the same way and provided with details of the MRC application procedures.

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7. FULL PROPOSALS

7.1	Successful applicants will hear that a full application has been invited within one week of CTAAC meeting. More detailed feedback will follow within 2 weeks, which will detail any concerns of the Committee that would need to be addressed in the full application. Unsuccessful applicants will be contacted within one week of CTAAC meeting and will be provided with feedback within 3 weeks of the meeting.
7.2	Details of how to submit a full application will be available as before. A checklist will need to be completed and submitted with each application covering the following issues: sponsorship, indemnity, MREC approval, DMC and Steering Group membership, compliance with research governance etc
7.3	Applicants will be notified of the deadlines for full proposals by CTAAC or MRC. Full proposals will be reviewed by external referees and will cover the same criteria as for the outline.
7.4	Following the meeting of CTAAC or the appropriate MRC Board, applicants will receive feedback that will detail any concerns which would need to be addressed before funding could be agreed. Unsuccessful applicants will be given detailed feedback including, if appropriate, how to re-apply (invited resubmissions only).
7.5	All trials funded or approved by CTAAC will, through the partnership arrangement, be eligible for treatment and service support costs.
7.6	All trials funded or approved by CTAAC will be added to the NCRN Trials Portfolio Database.

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8. SOURCES OF APPLICATIONS TO CTAAC

8.1

It is anticipated that CTAAC will be asked to review trials from a number of different organisations and individuals.

8.2

Applications are likely to come from the following sources: 8.2.1 NCRI Clinical Studies Groups The majority of trials reviewed by CTAAC are expected to have been developed or endorsed by NCRI Clinical Studies Groups. These groups will, over time, work closely with the York Evidence Based Review Group who will be responsible for carrying out evidence reviews and identifying gaps in the trials portfolio and with NTRAC. Whilst recognising the likely strengths of applications coming via these Groups funding decisions will be based solely on the criteria detailed in section 4.2. Irrespective of the source of an application the NCRI Clinical Studies Groups also have a responsibility for commenting on outline applications which have not been developed via one of their Groups (see 6.4). These comments will compliment, not duplicate, the CTAAC review (ie will focus on fit with existing portfolio and feasibility of recruitment targets). 8.2.2 Other Collaborative Groups It is recognised that there are a number of successful collaborative groups that may not fall within the purview of any one NCRI Clinical Studies Group. These may be long standing associations or collaborations formed to develop a particular trial. Applicants will be encouraged to discuss their study with the relevant NCRI Groups to ensure that there are no similar trials underway or in development and, where possible, to work with the appropriate Clinical Studies Groups. 8.2.3 International Collaborative Groups It is anticipated that some individuals/groups of clinicians/NCRI Studies Groups may wish to participate in international trials run by collaborative groups such as EORTC, GOG etc.. These trials, if approved, would become part of the NCRN portfolio and be eligible for NCRN support. Given that there is little or no opportunity to alter the protocols in such trials, applications for the adoption of an international trial by NCRN may be made by submitting a full proposal highlighting any NCRN resources that will be required (see overview diagram). Again, comments from relevant NCRI Studies Groups will be sought and applicants will be encouraged to discuss the proposal with the appropriate group at an early stage. Agreement to submit a full proposal directly to CTAAC without a prior outline must be agreed with the secretariat. 8.2.4 Applications from Individual Clinicians or Units Applications from individuals, mainly clinicians working within academic units of oncology, who have no allegiance to any particular collaborative group will be considered. These trials may include preliminary studies testing proof of principle or feasibility and may recruit from a limited number of centres. It is recognised that such trials should form part of the NCRN portfolio and, where appropriate, have access to NCRN resources. However, applicants will need to demonstrate a commitment to take these studies forward to Phase III trials. It is not anticipated that CTAAC should support a large number of pilot studies. The proportion of NCRN resources that are used by individual networks to underpin proof of principle or feasibility studies will need to be considered and the balance between this type of activity and large multi-centre phase III trials will need careful monitoring. 8.2.5 NCRN Trials CTAAC will also consider applications for NCRN resources which do not have a call on the Committee’s budget (ie no associated research costs). These NCRN Trials, which may come from a variety of sources, from NCRI Clinical Studies Groups to individual clinicians, will be subject to outline approval in the same way as the majority of other applications (international protocol trials being the only exception to this rule). 8.2.6 Pharmaceutical industry supported trials Industry supported, academic led trials of licensed compounds will be an important part of the NCRN trials portfolio. Only trials in which are investigator led where the ownership of the data lies with the Investigator/academic unit will be reviewed by CTAAC. Irrespective of whether of not the trial has financial implications for CTAAC it will require review at the outline stage. 8.2.7 Sub Panels of CTAAC The process of adopting trials that do not require specific additional resources, such as international inter-group studies, and approving individual or Unit studies that should become part of the NCRN portfolio may contribute a heavy organisational burden and workload. It would be unacceptable for this to generate delays or deferments and the option to create a sub panel to carry the workload with cross-membership with CTAAC and common standards will be considered. However, any mechanism of this type will need to demonstrate compliance with current competitive standards for access to NCRN resources. It should be stressed that this is not intended to cover the full range of applications which may be reviewed by CTAAC. If unsure, individuals are encouraged to discuss the suitability of potential proposals with CTAAC secretariat.

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9. REVIEW OF THE NEW ARRANGEMENTS

It is recognised that the processes described in this document must evolve and remain responsive to the needs of the research community and key stakeholders. In recognition of this, it has been agreed that these arrangements will be jointly reviewed by CRUK, LRF and MRC after three years to ensure they are meeting the aims and objectives of NCRI partners.

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