For the first time in the history of science, the scientific community has reached a great capacity to collect, analyze and report clinical data, the so called big data. However, there was no substantial change in the way we run clinical development in oncology, based on the randomized clinical trials paradigm, crystallized on a strategy designed 4 decades ago. This paradigm, although having the great merit to push forward the use of novel therapeutic agents, may not longer be the best option to deliver efficacious and safe drugs to the patients Few examples may bring some light on the issues we face today: • A rare lymphoma study, lasted more than 10 years, where the positive results will not be able to provide a game change in the therapeutic options of the disease, besides the well-known efficacy of the novel compound • A solid tumors study, where the OS of subjects having as bestresponse stable disease was equal or similar to OS of subjects having as best response progressive disease, raising questions about the impact of subsequent treatment, the difference between a stable and a slightly worsened disease and the ability of our tools – Recist – to detect these details • A solid tumors study, where the lack of ability to define the right biomarker or mutation to identify the population that may have maximum benefit from the treatment, lead to the failure of the entire trial These points, added to the huge cost of developing a novel treatment, may lead to an increase rate of failure or, even worse, to waste too much time waiting for the best treatment to reach the patients in need. We believe that a new paradigm should be developed, based on the points below: Defined endpoint should be established for every disease at every stage, is an increase in QoL more meaningful than a irrelevant survival increase in a cancer terminal patient? An improvement in PFS in disease where the survival is measured in years is

E.R.D.E.-AAK-Diagnostik GmbH is an independent, privately funded research and diagnostics laboratory specialised in agonistic autoantibodies against G-protein-coupled receptors (agAAB). For 25 years, it has focussed on these autoantibodies, which target receptors involved often triggered by viral infections. What scientific specialization defines E.R.D.E.-AAK-Diagnostik GmbH’s long-term research and diagnostic focus? The first 10 years of the laboratory focused on basic research of G-protein coupled receptors (GPCR), an important family of membrane proteins that transmit extracellular signals into cells. The GPCR superfamily includes several hundred receptors found in all human and animal tissues. In 2012, Robert J. Lefkowitz and Brian K. Kobilka received the Nobel Prize in Chemistry for elucidating the function of G protein-coupled receptors. They mediate the effects of various signalling molecules, such as hormones and neurotransmitters. GPCRs regulate nearly all bodily functions, controlling physiological processes and playing a central role in pathological conditions. They are primary targets for pharmacological therapies. Using the alpha-1 adrenergic receptor as an example in an animal model, E.R.D.E.-AAK-Diagnostik GmbH demonstrated that the respective agonistic autoantibody reduces blood flow and decreases the number of intact blood vessels. This GPCR regulates myocardial contractile function and glucose metabolism..