DOI: 10.25934/pr00009399
title: A novel, evidence-based approach to clinical trial design in patients with advanced liver cancer (hepatocellular carcinoma); single arm studies with a virtual control group 

description: We work on primary liver cancer, that is, a cancer that starts in the liver – also known as hepatocellular carcinoma (HCC). Worldwide, it is a common cancer that is usually rapidly fatal. It is predicted that by 2025 there will be more than one million cases occurring each year. The number of people developing this cancer is rising very fast. Sometimes HCC can be cured by surgical removal but usually it is too advanced for surgery to be effective by the time it is diagnosed. In the absence of physical removal of the tumour by surgery or other methods we rely on drug-based approaches such as chemotherapy,  immunotherapy or targeted drugs. Chemotherapy works by stopping cancer cells from multiplying, which prevents them from growing and spreading in the body. Immunotherapy works by boosting the patient’s own immune system to attack the cancer cells. Targeted drugs work by targeting the differences in cancer cells that help them to grow and survive. Slow but steady progress is being made in this area. But the progress is impeded because of the cost and complicated nature of the clinical trials that need to be carried out before a new drug can be introduced into practice. In the current research setting a clinical trial compares the outcome, usually length of survival, of patients being given a ‘new drug’ to patients being given the current ‘standard’ treatment, known as the 'standard of care'. Within a clinical trial this latter group is called the ‘control’ group’. Typically, such a trial will involve 500 -1000 patients, usually half in the ‘treatment’ and half in the ‘control’ group.

To aid the development of chemo- and immuno- therapy, we have built statistical models that can predict survival of any group of patients with HCC from measurement of certain clinical or laboratory features such as tumour size or levels of some proteins in the blood and any drugs they are being treated with. Using such models, we can compare the effectiveness of new potentially valuable drugs, to the current standard treatments without the need for a ‘control group’. Such a change in practice would dramatically decrease the cost of clinical trials which are extremely expensive and complicated. To accomplish this, we are requesting access to the control arms of early HCC trials (i.e. particularly trials undertaken before the current standard of care became available) in which a group of patients who were not offered active treatment were studied. We are also requesting data from clinical trials with the current standard of care treatments (sorafenib or combined treatment with atezolizumab and bevacizumab). Sorafenib is a targeted drug that works by stopping the signals that tell cancer cells to grow, and stops cancer cells forming new blood vessels, which they need to be able to grow. Bevacizumab is also a targeted drug that blocks a particular protein preventing the cancer from forming new blood vessels so it cannot grow. Atezolizumab is an immunotherapy drug that works by blocking a protein that stops the immune system from finding and killing cancer cells.