A debate to understand one of the key steps of medicine development 

Mirella Orsi

Primary endpoints in Oncology Clinical Trials” is the title of a lecture organized by The Italian Medical Society of Great Britain (IMSoGB) at the Italian Cultural Institute in London. This is only one of the many cultural events organised by IMSoGB, to promote new collaborations among doctors and to spread medical knowledge .This topic could seem just for experts. However, this debate was a chance to learn more about one of the key steps in the medical research and development. The speakers, all members of IMSoGB and all international experts talked from three different perspectives about
1. · For the clinician’s point of view,Professor Riccardo Audisio, MD, FRCS and President of the European Society of Surgical Oncology (ESSO).
2. · For the regulatory Body’s point of view, Prof. Guido Rasi, Former Executive Director of European Medicines Agency.
3. · For the healthcare industry‘s point of view, *Dr. Lucio Fumi Head, Medical Affairs*, International Oncology, Terumo.

However, what are the clinical trials? What are the primary endpoints?
Why they are so important?
Well, let’s see…

Clinical trial’s purpose is data collection to evaluate the effectiveness and safety of medications or medical devices. Clinical trials are used to determine whether new biomedical or behavioural interventions are safe and effective.Furthermore, they are used to compare a new treatment with the standard ones. Therefore, clinical trials are essential in medical research and development, because without them there would never have been any advancement in medicine.Clinical trials are usually conducted in four phases.
The potential treatments, found interesting in the pre-clinic studies, need to successfully cross the perilous “Funding Valley of Death,” to be tested in the clinical trials. As Dr Fumi says,”the image of the Valley of Death is often used to describe graphically the lack of continuum between development and marketing”. In fact, many promising potential drugs, devices, or other potential treatments are never tested in clinical trials due to lack of funding or other business difficulties. In many cases, further financial support or partnerships are needed to help “bridge the gap” across the “Funding Valley of Death” to begin Phase 1 Clinical Trial.

Endpoints are results, conditions or events associated with individual study patients that are used to assess study treatments. The Primary Endpoint is the single endpoint parameter for rejection of the null hypothesis. A trial may also define one or more secondary endpoints.These typically include secondary efficacy measures (additional evaluations designed to assess the clinical effectiveness of the drug in controlling disease) and safety endpoints (designed to measure tolerability and safety of treatment over the period of study.These parameters should be easy to diagnose, free of measurement error and reliable with repeated measure. The endpoint has to be clearly set ahead and requires no subjectivity.It is very important to say that designing an oncology clinical trial is more difficult than other clinical trials.

Firstly, as we know, cancer is a group of very articulate and complex diseases and the therapy can be often a combination of surgery, radiotherapy and chemotherapy, so, the overall therapy changes for every patient.Secondly, one phase of testing a new drug involves a comparison between a group that take the drug and a group taking a placebo.However, there is the ethical problem of leaving cancer patients without treatment.Another important point is the difference of the regulatory body in EU and USA. Often, FDA uses as primary endpoint the Overall Survival( OS)(1) is often reported as a five-year survival rate, i.e. percentage of patients alive five years after diagnosis or treatment.
The most interesting point of this lecture is that all three speakers agree about the need to use different primary endpoints for the oncology clinical trials.
I had the great pleasure to interview Dr. Fumi, and as he said, using alternative primary  endpoints in oncology clinical trials can be very useful to the development of new treatments. It is also important to use short-term endpoints in the oncology clinical trials, because this is the best way to assess the treatment step by step, he added.
Talking about alternative primary endpoints, one that is used in the UK is *QALY* (quality-adjusted life year or quality-adjusted life-year) that is a measure of disease burden, including both the quality and the quantity of life lived. This is a very engaging primary endpoint because the quality of life is one of the cancer patients’ major concerns. In addition, *Quality of Life* and *Tumour response* have to be taken into consideration more than in the past.

Designing primary endpoints is one of the most challenging issues related to the clinical trials. In fact, the wrong choice can delay the development of new drug or invalidate a study. For this reason, the choice of clinical efficacy endpoints remains a controversial topic.
To conclude, it is beyond question, that a key to design a successful clinical trial is the professional partnership of the doctors with different backgrounds and specialisms. The collaboration is essential to cover all the aspects of these research studies. The clinic, the regulators and the pharmaceutical point of view are all equally important to guarantee the development of the best treatment. The balance between benefits and risks has to be considered, because, it occupies a central place in licensing and approval decisions, Prof Rasi said. The priority, as they said, is always to identify and promote a safe, effective patient-centred cancer care.

(1)Overall Survival is the percentage of patients alive at a defined period of time after diagnosis or, in treatment studies, the percentage of
patients alive at a defined time after initiation of the treatment.

Published on ItaloEuropeo Saturday, 16 May 2015