How improving Complex Innovative Design trials could get innovative treatments to patients faster

Recommendations have been published in the British Journal of Cancer on how best to conduct Complex Innovative Design (CID) trials. Dr Ali Hansford, Head of Regulatory Strategy Policy, looks into these recommendations in more detail.

As a scientist doing research, you are generally taught to investigate one thing at a time. Identify a problem, review what’s already known and then test different things that impact on that problem to try and find a solution. That’s also how clinical trials have traditionally been designed for many years meaning new medicines have been taking an average of 12 years to reach clinical practice. (1)

But there is another way of conducting trials where scientists investigate multiple clinical questions at the same time. In Complex Innovative Design (CID) trials you can efficiently combine multiple research questions into a single study, as well as having the flexibility to add new, or stop existing, parts of the study whilst it’s ongoing. It’s a rapidly expanding method of research, and it has the potential to get new medicines to patients faster.

One of the earliest examples of a CID trial was the international PROFILE 1001 non-small cell lung cancer study designed to investigate crizotinib. As data started coming in, it was found that a subset of patients in whom the drug was working all had the same genetic change (known as the ALK fusion gene). The study was changed so more patients with this genetic change were recruited into the trial. This led to the medicine receiving approval from the EU in 2012 - only 5 years after the discovery of the fusion gene.

Knowledge and awareness of CID trials has increased over recent years, notably since Dame Tessa Jowell gave an emotional speech in the House of Lords, almost 2 years to the day, calling for the increased use of adaptive trials.

In early 2018, I was invited by the Experimental Cancer Medicine Centre (ECMC) to join a Working Group to look at how CID trials can work better for everyone. Alongside other members from regulatory agencies, pharmaceutical companies, Government, charities, Research Ethics Committees, universities, the NHS and patient groups, we set out to identify recommendations to navigate the hurdles often encountered when conducting CID trials.

It’s essential this work was done – the process of researching and developing new medicines is time-consuming, costly, and there is a high rate of failure. Anything we can do to improve this is a win for patients, the NHS and industry.

In brief, the ten recommendations published today are:

1. Trial Planning and Design: Engage with regulators and health technology assessment bodies as early as possible. This early mutual understanding will maximise the chance of a successful clinical trial application and future marketing authorisation and reimbursement decisions.
2. Protocol Development: Clearly describe any possible future changes to the study from an early stage. This will reduce the cost and time to make these changes, if and when required.
3. Patients and public involvement (PPI): May require specific training, support, and perhaps also accreditation. This applies to patients and the public who are involved in reviewing patient information sheets, which can be more complicated for CID trials.
4. Patient Facing Documentation: Provide three-part patient information comprising of an invitation document, a study arm-specific document and a handbook. A single patient information sheet is likely to be too long and complicated for a CID trial. Also consider formats other than the written word, such as videos.
5. Statistical Considerations: Ensure the study is designed to provide the flexibility to incorporate individual variations for different treatments, diseases and molecular characteristics as the study progresses. The heavier statistical workload to deliver CID trials should not be underestimated when considering the resources required.
6. Defining Leadership and Oversight: Convene an experienced Trial Management Group to oversee the study. As CID trials may ask multiple questions, it might be necessary for the trial lead to be shared or transferred between specialists over time.
7. Dissemination of Results: Timely reporting of data when a research question is answered, or a study arm is completed. Promptly sharing findings with the scientific community reduces the risk of a different research group duplicating effort.
8. Staff Training: Include training specifically for CID trials in the curricula of relevant health care professionals to ensure appropriate resources are in place to deliver CID trials.
9. Approval and Reimbursement Decisions: Utilise existing accelerated access initiatives to ensure effective medicines discovered through CID trials are rapidly approved and made available to patients.
10. Evaluating the impact on public health: Conduct impact analyses on CID trials to ensure they deliver on their promise to provide safe and timely access to medicines. No formal comparisons of CID trials with traditional studies have yet been performed to confirm that they provide a faster route to patients.

Next steps

The Working Group is now calling on clinicians, funders, regulators and the pharmaceutical industry to get behind the recommendations and work together to rapidly implement them.

Progress is being made – following the publication of the Government’s Life Sciences Sector Deals (2,3), significant action has been taken over the last two years to strengthen the environment for clinical trials. Most recently, MHRA launched a survey in order to gather feedback on their advice and services, with a particular focus on novel designs, with a view to transform the services they offer in the future. But there is still much more to be done in order to “consolidate our world-leading position in delivering novel and innovative trials” – a commitment in Sector Deal 2.

The UK’s success in early science has been built on attracting investment and research activity from global pharmaceutical companies to our world-famous universities and research centres. The industry runs thousands of trials around the world at any one time (4) and invests significantly into UK R&D. At £4.5 billion a year (5), the industry invests far in excess of any other sector.

If we are to continue attracting international pharmaceutical companies, we must maintain and strengthen the UK offer for clinical research.

By building on the UK’s wealth of expertise in designing and executing CID trials, today’s recommendations will ensure that Government and industry can deliver on their commitment to further strengthen the UK clinical research environment.

References

1. Association of the British Pharmaceutical Industry. Time to flourish – Inside innovation: the medicine development process. 2012.
2. HM Government. Industrial Strategy: Life Sciences Sector Deal. 2017.
3. HM Government. Industrial Strategy: Life Sciences Sector Deal 2. 2018.
4. Association of the British Pharmaceutical Industry. Clinical trials - How the UK is researching medicines of the future. 2019.
5. Office for National Statistics. Business enterprise research and development, UK: 2018. 2019.