New recommendations for conducting complex innovative design trials - hear from the authors
14 Dec 2022
The ECMC’s Complex Innovative Design (CID) trial consensus paper was published in January 2020 and has since been one of the BJC’s most popular downloads. At the time of its publication the authors were unaware that the pandemic was only weeks away and that complex innovative design (CID) studies like RECOVERY would become household names in combatting COVID-19. In honour of BJC’s recent 75th anniversary the writing group has recently published a follow-up commentary. We invited the authors to discuss these publications and the future for CID trials.
Why did you start the CID writing project? (Sarah Blagden, University of Oxford)
In May 2018 the ECMC held a consultation at its annual meeting around the challenges of conducting platform, adaptive, Multi-Arm Multi-Stage (MAMS) and modular, collectively termed “CID”, studies. Centres with experience of these trials described their administrative burden – not least in managing the multiple major protocol amendments they generate. Pharmaceutical companies were concerned with potential delays to the release of interim results, ethics committees were daunted by the volume of paperwork and the Medicines and Healthcare products Regulatory Agency (MHRA) were concerned about requests to authorise ‘never-ending’ CID trials without defined endpoints. To address these concerns, the ECMC appointed a working group comprised of the Medicines and Healthcare products Regulatory Agency (MHRA), National Institute for Health and Care Excellence (NICE), National Cancer Research Institute (NCRI), Department of Health, Health Research Authority (HRA), Association of the British Pharmaceutical Industry (ABPI), patient representatives and UK trialists. It immediately became apparent that there were mutually acceptable solutions to many of these challenges that we captured in our CID consensus paper. The adoption of CID trials during the pandemic has erased concerns they are too unwieldy to test innovations in real-time. However, the investigators achieved this fleet-footedness by pragmatically reducing bureaucracy, using methods highlighted in our follow-up commentary.
In May 2018 the ECMC held a consultation at its annual meeting around the challenges of conducting platform, adaptive, Multi-Arm Multi-Stage (MAMS) and modular, collectively termed “CID”, studies. Centres with experience of these trials described their administrative burden – not least in managing the multiple major protocol amendments they generate. Pharmaceutical companies were concerned with potential delays to the release of interim results, ethics committees were daunted by the volume of paperwork and the Medicines and Healthcare products Regulatory Agency (MHRA) were concerned about requests to authorise ‘never-ending’ CID trials without defined endpoints. To address these concerns, the ECMC appointed a working group comprised of the Medicines and Healthcare products Regulatory Agency (MHRA), National Institute for Health and Care Excellence (NICE), National Cancer Research Institute (NCRI), Department of Health, Health Research Authority (HRA), Association of the British Pharmaceutical Industry (ABPI), patient representatives and UK trialists. It immediately became apparent that there were mutually acceptable solutions to many of these challenges that we captured in our CID consensus paper. The adoption of CID trials during the pandemic has erased concerns they are too unwieldy to test innovations in real-time. However, the investigators achieved this fleet-footedness by pragmatically reducing bureaucracy, using methods highlighted in our follow-up commentary.
Are CID trials ever likely to replace individual cancer studies? (Mark Lythgoe, Imperial College)
Global drug regulators, such as the MHRA and US Food and Drug Administration (FDA), are increasingly backing CID trials to support new cancer drug approvals; for example, the FDA now offers a dedicated pathway for CID trials. This is feeding back positively to academics, funders (e.g., charities) and collaborators in the pharmaceutical industry. In terms of fully replacing individual cancer studies, I think there will always be a place for these, however I can see a scenario where CID trials are interfacing and working very closely with individual cancer studies.
Global drug regulators, such as the MHRA and US Food and Drug Administration (FDA), are increasingly backing CID trials to support new cancer drug approvals; for example, the FDA now offers a dedicated pathway for CID trials. This is feeding back positively to academics, funders (e.g., charities) and collaborators in the pharmaceutical industry. In terms of fully replacing individual cancer studies, I think there will always be a place for these, however I can see a scenario where CID trials are interfacing and working very closely with individual cancer studies.
What’s next for CID studies? (Francois Maignen, NICE)
Despite the hype of CID trials, most new medicines approved in the UK have been tested using conventional clinical trial designs. We hope that, in the future, training and regulatory guidance will be made available to improve the uptake of innovative CID trials. These should hopefully be combined with other approaches including electronic reporting of patients reported outcomes (ePROs), virtual, decentralised or siteless clinical studies. However, these approaches require closer communication and coordination between stakeholders (such as sponsors, patients, ethics committees, regulators and health technology agencies).
Despite the hype of CID trials, most new medicines approved in the UK have been tested using conventional clinical trial designs. We hope that, in the future, training and regulatory guidance will be made available to improve the uptake of innovative CID trials. These should hopefully be combined with other approaches including electronic reporting of patients reported outcomes (ePROs), virtual, decentralised or siteless clinical studies. However, these approaches require closer communication and coordination between stakeholders (such as sponsors, patients, ethics committees, regulators and health technology agencies).
What challenges do ethics committees face when reviewing CID trials? (Stephanie Ellis, HRA)
By definition, information around CID trials is complex with a fair amount of technical language. We have proposed the inclusion of explanatory route maps, signposts and simple diagrams. In addition, trialists should provide RECs with a clearly defined statement of the overall purpose of the trial and how each arm fits into this central idea. We are reassured when we can see that the researcher has thought about how to help participants that are randomised into an ineffective arm. Finally, a plan for informing participants how they helped and what has been learnt from the CID trial is welcomed.
By definition, information around CID trials is complex with a fair amount of technical language. We have proposed the inclusion of explanatory route maps, signposts and simple diagrams. In addition, trialists should provide RECs with a clearly defined statement of the overall purpose of the trial and how each arm fits into this central idea. We are reassured when we can see that the researcher has thought about how to help participants that are randomised into an ineffective arm. Finally, a plan for informing participants how they helped and what has been learnt from the CID trial is welcomed.
How likely is it that “lessons from COVID” will be learned as we return to business as usual (Stephanie Ellis, HRA)
The most important lesson I have learnt as Chair of the COVID Challenge Studies Research Ethics Committee is that although some have said that COVID is a great leveller the statistics reveals dramatically just how uneven the impact on people has been. The same applies to cancer and highlights the importance of delivering clinical research more evenly to address these inequalities. This topic is also a focus of our recent commentary.
The most important lesson I have learnt as Chair of the COVID Challenge Studies Research Ethics Committee is that although some have said that COVID is a great leveller the statistics reveals dramatically just how uneven the impact on people has been. The same applies to cancer and highlights the importance of delivering clinical research more evenly to address these inequalities. This topic is also a focus of our recent commentary.
Overall, as trial centres recover from the pandemic and regain their momentum, CID studies can now be considered realistic options for improving the speed and delivery of cancer drug development.
Stephanie Ellis, HRA
“I was delighted to help the ECMC in preparing the guidance on CIDs, and then to begiven the opportunity to help update it. The Network is showing valuable leadership in helping promote these applications, but also showing how best to explain these important trials. This is important work that the HRA wants to promote and celebrate: it will help the UK maintain its leadership in the world of medical research and in finding ways to combat cancer .”
Dr Ali Hansford, Head of Regulatory Strategy Policy at The Association of the British Pharmaceutical Industry (ABPI) and author on the paper
“The pandemic proved that innovative approaches in clinical research can achieve fast results for patients. We must now seek to build on these experiences and continue to streamline and simplify the process of designing and delivering complex innovative design (CID) clinical trials, while also maximising the opportunity for patients to get involved in research. Doing so will ultimately speed up innovation and deliver needed treatments into the health service more quickly.”