Parts of this chapter have been reproduced from Brown et al.20 This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: https://creativecommons.org/licenses/by/4.0/. The text below includes minor additions and formatting changes to the original text.
Reflections from stakeholder groups
Complex, adaptive stratified medicine studies are feasible but delivery can present numerous challenges. We have already published a series of papers on the practical aspects of running these sorts of complex platform trials.119–122 With FOCUS4 now closed and learn more from the 10-year experience and provide insight for those in the research community hoping to undertake similar studies, we sought feedback from a number of stakeholders who were involved in the delivery of the trial. Each of the following eight stakeholder groups were asked to provide learning points from their experience: (1) co-chief investigators, (2) subtrial chief investigators on the TMG, (3) clinical research fellow trainees, (4) MRC CTU, (5) biomarker-testing laboratories, (6) patient/carer representatives, (7) oversight committees and (8) funders.
In addition, a participating site survey was distributed via site principal investigators to understand the experiences of site staff. Principal investigators at each of the 88 sites that registered at least one patient were sent a link to an anonymised survey, asked a series of questions about their practice and encouraged to provide additional comments on aspects of the trial that had worked well and not so well.
Feedback from stakeholder groups
Feedback was received from 19 out of 38 individuals, including at least one representative from each of the eight stakeholder groups. Experiences were very positive despite an acknowledgement of the substantial challenges encountered. There was considerable overlap in a number of the points raised, and the comments naturally grouped into three main areas: (1) resource and infrastructure, (2) biomarker-testing process and (3) trial design. A summary of the 20 learning points synthesised from the feedback is presented in Table 13. The most consistent learning points related to the following four key areas:
- Understand resource capacity and ensure that adequate funding is secured for staff. These designs probably save time and speed up getting answers but still require similar amounts of resources per research question. The challenge for funders is to find a mechanism for funding and review of trial adaptations that facilitates delivery and minimises burden, while also managing the risks involved.
- The biomarker-testing process should be kept as simple as possible and, for the UK, as much as possible should be kept within the NHS infrastructure.
- Position the trial within the optimal phases of drug development and try to ensure that there are parallel research initiatives to support the trial in relation to ever-shifting biology and preclinical workup. FOCUS4 may have worked better as a Phase I/IIb platform trial.
- Platform trials need to be nimble and able to adapt quickly with emerging new biological discoveries. This is difficult in a sometimes turgid clinical trial regulatory framework.
| Learning point | Resource and infrastructure |
|---|---|
| 1 | Secure adequate funding |
| 2 | Delivering all desired outcomes for a platform trial is clearly challenging. The challenge for funders is to find a mechanism for funding and review of adaptations that facilitates delivery and minimises burden while also managing the risks involved |
| 3 | Ideally, these trials should be conducted only in CTUs that have good core funding resources and a ballast of trained in-house trial and data managers who can be drawn on temporarily at times of intense activity |
| 4 | Activate fewer sites and stagger opening |
| 5 | Leadership: the chief investigator role is paramount and must not be underestimated, with far more pressure than being a CI on a more standard trial. An engaged and enthusiastic core TMG is vital |
| 6 | The CTU staff must feel comfortable and encouraged to escalate any site issues to senior TMG members quickly |
| 7 | A great training experience for CTU staff and clinical research fellows. Provide basic clinical trial training for research fellows to aid learning |
| 8 | Site enthusiasm was inconsistent between registration and randomisation. Understand local motivations or obstacles to recruitment |
| 9 | Trial longevity can lead to poor continuity of CTU and site staff, which is disruptive in a complex trial in which the design keeps adapting |
| 10 | For trials that last many years, trial participants need better opt-in/opt-out arrangements on how they can be kept informed on trial progress |
| Biomarker-testing process | |
| 11 | Regular quality assurance and review of sample-testing processes to identify any glitches that require modification |
| 12 | Important to spend adequate time on biomarker work-up and optimisation as well as understanding prevalence early on before taking further |
| 13 | Keep biomarker testing within the NHS infrastructure as much as possible with as few middle men as possible to avoid data privacy obstacles |
| 14 | Important to have an engaged and dedicated biomarker team who can manually step in and overcome any delays to prevent patient distress |
| Trial design | |
| 15 | The MAMS adaptive design worked well at cutting losses on poorly performing drugs early |
| 16 | The requirement for a control arm in each comparison was important in determining any prognostic biomarker effects |
| 17 | The need for a catch-all non-stratified trial (FOCUS4-N) proved to be successful at maximising trial opportunities for patients |
| 18 | Important to get the protocol structure right and consult with regulatory bodies on advice for what is acceptable within the design |
| 19 | The main issues were mostly related to pharma engagement and drug-target identification in the specific disease setting of the study. Earlier engagement in the developmental pathway for new therapies is required so that when the therapy is ready to drop into a trial, all parties have been engaged and involved with the biomarker optimisation and early drug activity assessments |
| 20 | Funding of complementary feeder collaborations, such as S:CORT30 (which focused on understanding the biology) and ACRCelerate31 (which focused on preclinical novel agent development), might have been beneficial if run in parallel with FOCUS4 |
Results from the site survey
Feedback was received from 52 out of 88 sites (59%), with representation from all level 1, level 2 and level 3 sites. Sites were asked about standard treatment for patients with unresectable stage 4 metastatic CRC; the majority used either a block of chemotherapy followed by a complete break or intermittent chemotherapy with a complete break. In some settings, treatment to progression was considered, as well as maintenance chemotherapy, but both were rare. Most sites were supportive of using the maintenance setting to test new therapies.
The remaining results of the survey have been summarised in Table 14 and show that, although sites experienced a number of challenges in delivering FOCUS4, sites were positive about their involvement and supportive of the use of these trials in the future, if resourced adequately.
| Question and response | Take home message |
|---|---|
| Did inability to restart an EGFR inhibitor impact on patient selection?Agree/strongly agree: 68%Neutral: 14%Disagree/strongly disagree: 18% | NHS rulings on the use of EGFR inhibitors restricted recruitment and may have been a barrier to finding alternative or better therapies relevant in the RAS wild-type group |
| Was having an unselected FOCUS4-N trial important?Agree/strongly agree: 71%Neutral: 25%Disagree/strongly disagree: 4% | An important aspect of the design that was strongly supported by sites and patients |
| What were the advantages and disadvantages of conducting this trial in the maintenance setting? | Advantages:Fitter patientsLess acquired drug resistanceInduction chemotherapy allowed time for biomarker testing without delaying treatment startLess end organ impairmentPatients felt they were ‘trying something’ when otherwise might be having a breakDisadvantages:NHS England rules preventing EGFR inhibitor reintroductionA more challenging route to registration for successful agentsAdditional hospital time or toxicitySome patients progress during induction treatment and become ineligible |
| Did you experience any particular study challenges? | Staff and infrastructure:Delays with R&D approvalLimited nursing support particularly at level 1 sites for our networkMaintaining team motivation when novel arms not openSome challenges referring from a level 1 site to a level 2 or level 3 siteTrial assessments:Poor capacity for RECIST reportingNovelty of the trial biomarker panel became diluted as NHS testing rolled out |
| What went well? | Excellent CTU communications (e.g. response to queries, newsletters)Novel design of an adaptive platform trial in a common solid tumour: first of its type in the UKEasy to recruit with the window to request biomarker testingEngaged all geographical areas within the UK with the level 1–2–3 designPatient information sheets were well developed |
| Are platform trials the future? | Grossly underfunded but definitely the best way to proceed compared with running endless small trials in small subgroupsFunders should have supported funding for fresh biopsies and additional translational workSpeed and efficiency of adding arms with protocol amendmentsPlatform allows for substudies (e.g. exercise, PET, CT DNA) |