The Goldilocks Effect


Advances in the delivery of precision medicine trials in the UK have sparked interest in the commercial world.


The concept of precision medicine* is not new, but generating the scientific evidence to drive the concept into everyday clinical practice is challenging, to say the least. Traditional approaches, involving multiple phase trials in different hospitals and at different times are reliable but take time, even more so when the biomarker that predicts good response is rare. A new, more efficient approach to testing stratified novel therapeutics is underway in the UK which also has the potential to achieve a faster route to drug registration and availability to patients.

Molecular oncology (the study and treatment of cancer and tumours) has seen an explosion of biologic knowledge over the last 10-15 years. Since understanding the sequencing of the first genome fundamental scientific discoveries are being made at a staggering rate. Consequently oncology is widely recognised as being the vanguard of precision medicine research.

Professor Rick Kaplan is a global innovator when it comes to cancer research. A medical oncologist with over 40 years’ experience in clinical research, he’s currently a senior leader at the Medical Research Council Clinical Trials Unit and also works as Honorary Consultant in Oncology at University College London Hospital:

“The ‘hit and miss’ process which led to perhaps a dozen potential treatments per year being taken into clinical trials has been replaced by a conveyer belt of literally hundreds of targeted, experimental cancer drugs. The chances of these drugs targeting the intended cancers are much higher than anything that we could manage by previous methods. What we need now is a logical, systematic way to quickly and efficiently find out which drugs hit which tumours in which patients.”

According to Professor Kaplan the UK is the ideal place to do this. Having worked in the USA for 30 years before settling in the UK in 2004, and having also served on advisory committees and panels for multiple government agencies, professional organisations and clinical trials organisations in North America, Europe and Australia, he’s well placed to describe what he calls ‘The Goldilocks Effect’:

“Firstly, the UK is large enough to have adequate pools of patients. But it’s also small enough to foster a real motivation and necessity for people to work together; clinicians, academics, life-science companies and charities. This is in contrast to, say, the US, which is so large and so decentralised that it discourages such wide ranging collaboration.

“Secondly, in the UK brand new drugs are not automatically available in the National Health Service (NHS) which presents us with a window of opportunity during which we can begin to unpick which drugs actually work in which patients. By comparison, in the US patient demand combined with commercial forces mean that drugs are used in a wider patient population than the original intended target and subsequent information on effectiveness can be skewed. This is especially true if a drug is featured in the media.

“Another reason is the research infrastructure provided by the Government-funded National Institute for Health Research (NIHR), particularly the NIHR Clinical Research Network and the Experimental Cancer Medicine Centres – key components in facilitating fast and efficient clinical research. The reality is that precision medicines increasingly need to draw upon smaller and smaller sub-populations  of a particular disease which can be identified by specific biomarkers. So to get the recruitment levels required to make the study results significant the net needs to be cast wider.

“The Clinical Research Network, which is the research delivery arm of the National Health Service, can facilitate a hub and spoke approach which allows patients who are keen to participate in a trial to be referred on to the trial site at a specialist centre such as one of the 18 Experimental Cancer Medicine Centres. Again this doesn’t happen easily somewhere like the US because of the commercial market.

“So to summarise it’s not too big, not too small, and the regulatory environment is just right. It’s a bit like Goldilocks getting her hands on the perfect bowl of porridge – the UK is fertile ground for delivering precision medicine trials.”

And the green shoots of precision medicine trials are beginning to show. Two pioneering projects are now underway in the UK.

Precision definition FWidth3

“Focus4 and The Lung Matrix are both ‘platform’ trials”, Professor Kaplan explains. “By this we mean a framework of trials in a specific disease area. Focus4 looks at colon cancer and The Lung Matrix targets lung cancer.

“Starting a new trial is usually a two year process but in our approach, when a new drug/biomarker combination is developed, we don’t start a new trial, we simply add a new arm to the existing platform by means of a protocol amendment and avoid the two year delay.”

Professor Gary Middleton is a Consultant Medical Oncologist and Chief Investigator for The Lung Matrix. He’s also a member of the trials management group and Chief Investigator for one study arm of Focus4. He explains how the platform approach tips the screening versus eligibility balance favourably:

“The Lung Matrix is intrinsically linked to Cancer Research UK’s Stratified Medicine Programme 2 which is genetically screening up to 2,000 lung cancer patients a year. Pharma companies seeking a biomarker in a rare patient cohort may have to screen 100 patients to find two or three eligible patients. Alternatively they can add the study to our platform and tap into our screening programme and we will be able to identify that rare two or three per cent in the 2000 plus patients we are screening. Pfizer and AstraZeneca are firmly on board and we have a whole host of other companies interested.”

Another common thread of both platform programmes is flexibility. Professor Kaplan continues:

“Focus4 is essentially a first  line treatment study . There are currently three biomarker specific arms and a non-biomarker chemotherapy arm meaning that every single patient screened is eligible to join the trial. Four more biomarker arms are in the pipeline, and if any drug fails to suggest benefit in a cohort, other new drugs can then be tested for new patients with that biomarker.

“Also, there is built-in flexibility that allows us to refine the biomarker definitions. So if we find that a patient with biomarker A is not going to respond to a particular drug unless they also have biomarker B, we can change that biomarker definition. The trial will adapt as the science evolves.”

There is optimism across the clinical community that this new adaptive approach will accelerate the discovery of a targeted therapy for colon cancer. In lung cancer, where attributable recognised targeted therapies already exist, Professor Middleton is also optimistic that The Lung Matrix – which currently has 20 arms and another two due to launch – will yield new targeted therapies and may even herald a shift away from the traditional four phase model of clinical trials:

“The general belief is that the only way you can get drugs to market is by doing large phase three style studies. But in lung cancer we have seen drugs successfully registered on the basis of 50 patients taking part in a well designed phase two study. The Lung Matrix aims to amplify that success by conducting many small studies simultaneously. Each arm will recruit around 30 patients. Naturally, some drugs will not show any activity. But where we see good levels of positive activity we are hoping that with compelling biology evidence we may, in some cases, have a faster route to registration.”

Professor Tim Maughan is Chief Investigator of Focus4. He was one of the architects of the first cancer clinical research network (in Wales in 1998) and subsequently helped develop clinical research networks across the UK. As interest in the platform approach grows in the commercial world Professor Maughan echoes the words of Professor Kaplan – that the collaborative mind-set of the UK underpins its ability to conduct complex programmes of precision medicine trials:

“Under the auspices of the National Cancer Research Institute Clinical Studies Groups a number of groups and individuals have worked closely together for the last decade; Cancer Research UK, the National Institute for Health Research, the Clinical Research Network and the Experimental Cancer Research Centres, Biomarker Pathology Genetics Group, not forgetting the Clinical Trials Units. This collaborative framework of experienced clinical researchers has created a positive environment and given us the confidence, and the track record, to develop the platform approach and engage companies like AstraZeneca, GSK, Novartis, Bayer and Amgen.

“As clinicians this new direction is important. It enables us to get more molecular profiling of tumours and gain access to new drugs. The concept of one treatment for all patients of a particular disease is out-dated. These platform trials provide a flexible and rapid way of evaluating the activity of new approaches and testing them rigorously to demonstrate benefit.”

An article providing further background about how collaborative work helped to lay the foundations for this advance in clinical trial design is also available.
* Precision medicine, sometimes called stratified medicine or targeted medicine, is an emerging approach for disease prevention and treatment. It takes into account people’s individual variations in genes (genotype) and how their genetic make-up is affected by external factors such as environment and lifestyle (phenotype). This information is used to make decisions about which treatments will work best in which patients.