Illuminating ideas: Innovative clinical trial design

As we enter the era of precision healthcare, scientists and researchers are exploring new ways to evolve the drug development process so that treatment advances can be matched to specific patients and potentially reach them even earlier. Here, Dr Frank Hermann, International Medical Director GI Tumours at Roche, looks at some of the approaches that are currently being used.

All new medicines must be fully tested before they can be made available for patients, to ensure that they are both safe and effective for their intended use. Carefully conducted clinical trials with patients randomly assigned to two or more groups, each receiving either a new or approved medicine in order to establish which one is the superior treatment for a particular disease, have long been the gold standard to achieve this.

Dr Frank Hermann, International Medical Director GI Tumours

Traditionally, clinical trials are broken down into several different phases. Phase 1 trials are designed to establish what effects a new drug has on the human body, as well as the correct dosage. These trials are very small and typically consist of only 10-20 healthy volunteers.  Phase 2 trials are performed on larger groups - up to around 100 patients with a specific disease - to assess the medicine’s efficacy, safety and tolerability in that patient population. Phase 3 trials establish safety, efficacy and superiority over the current standard of care in hundreds, or even thousands, of patients and are generally used by regulators to determine if a drug should be licenced for use in patients.

Whilst this process has worked well for nearly sixty years, it is becoming less viable as we understand more about certain diseases. Cancer, for example is no longer defined in basic terms such as ‘lung cancer’ or even ‘non-small cell lung cancer.’ Each cancer type is actually a heterogeneous group of hundreds of different entities, each one caused by specific genetic changes (‘mutations’) and/or combinations thereof in the tumours involved. Having to potentially run ever more clinical trials for each cancer type, whilst also trying to identify and recruit relatively small groups of patients with the specific mutations in question, is making traditional Phase 1-2-3 clinical development increasingly difficult and time-consuming. Ultimately this could result in significant delays in an effective medicine reaching the patient.

To overcome this, researchers are exploring novel ways of evaluating new compounds and designing clinical trials. One way is the umbrella study, designed to test the impact of different drugs on different mutations in a single type of cancer (‘under the umbrella of one disease’). Patients are selected based on the genetic mutation most prominent in their tumour and treated with a number of medicines known to target this specific mutation. While umbrella studies can be complicated, they allow researchers to test a number of different medicines in patients with a similar disease; identifying patient subgroups who would most benefit from those medicines tested.

Umbrella studies are certainly a novel approach to drug development. They allow patients to be assigned a specific treatment based on the mutation profile of their tumour, thus personalising the approach with a higher probability of success. From a research point of view we can use these studies to test a variety of targeted medicines at the same time which gives us a much quicker indication of the best candidate medicine relative to a specific mutation.

Basket studies test the effect of a single drug or drug combinations on a specific mutation in a variety of cancer types (‘baskets’), allowing researchers to analyse each cancer type individually, as well as assess the impact of the drug or drug combinations as a whole. Using this approach, it is possible to combine what would have been multiple Phase 2 trials into a single study, thus greatly speeding up the development process and improving our understanding of the different types of cancer and expediting the delivery of an effective treatment to the patient.

Basket studies are focused on a single target that is evident across multiple tumour types, so a detailed understanding of tumour biology is essential. Unlike umbrella trials, they only include one investigational medicine, but if done correctly we can quickly identify its effects on several cancer types at the same time.

Adaptive study designs also have a role to play in enhancing the clinical trial process. Normal clinical studies have a number of pre-specified treatment arms in which patients receive a pre-determined therapy for a fixed period of time. With an adaptive study design, researchers can see how patients are responding to treatments whilst the study is running and can alter aspects of the study, such as the compounds being investigated, or add additional cohorts to incorporate the findings of current and future research. All of this allows the optimal treatment regimen to be determined quickly and efficiently.

Adaptive trial design gives the researcher more flexibility. Traditional clinical trials are rigidly designed to follow a specific protocol and do not take into consideration new scientific understanding and discovery. As the name suggests, adaptive trial designs allow for the trial to stay current with the latest updates, so that when the trial reports it isn’t already out-dated.

These and other innovations in clinical trial design have the potential to accelerate drug development so that the right therapies can rapidly be delivered to the right patients.

We believe that innovative approaches to clinical trial design will have a huge impact on how we develop new medicines. They factor in our growing scientific knowledge base, including our understanding of disease biology, and hopefully will allow us to tailor more treatments to more patients in the future. Roche is at the forefront of this approach because of our deep pipeline, our aptitude for designing viable treatment combination strategies, and our ability to develop companion diagnostics tests. By following this path, we will be able to reach more patients with meaningful treatments. You will certainly see much more from us in the future.