Change is Here, But Are We Ready for It?

The National Institutes of Health (NIH) defines clinical research as “Research with human subjects that is: Patient-oriented research. Research conducted with human subjects (or on material of human origin such as tissues, specimens, and cognitive phenomena) for which an investigator (or colleague) directly interacts with human subjects. Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual. It includes: (a) mechanisms of human disease, (b), therapeutic interventions, (c) clinical trials, or (d) development of new technologies” (1).

This seems clear and straightforward; however, as we continue to discover more about the genetic basis of disease and move ever more towards a personalized approach to diagnostics and therapeutics, the boundaries between what is defined as clinical research, and basic and translational research, are becoming blurred.

We have entered a new era in healthcare and medicine where patients’ tests are being used to not only inform treatment decisions, but also to develop our knowledge of disease and drive new research. Recent advances in oncology – for example in molecular intratumor heterogeneity and its impact on the pathogenesis of disease and treatment resistance – have given rise to patient-centric clinical research performed on solid tissues or blood (the so-called liquid biopsies), with the results being very specific to that donor patient. In this scenario, molecular analyses are performed to verify clinical cases and to assess efficacy of new treatment opportunities. This analysis is not limited to a few defined biomarkers only, though, it gives rise to subgroups of patients, whereby some may have intrinsic resistance to therapy from the beginning, and others later present an acquired resistance. This type of knowledge supports the need for ongoing molecular analysis through a patient’s treatment pathway with the definition of increasingly small groups of patients and suggestion of very specific combinatorial therapies. However, it also provides valuable information for the development of new therapeutics.

In anticipation of the growing importance of clinical research, the Organisation of European Cancer Institutes (OECI) (2) has developed a specific accreditation and designation programme for comprehensive cancer institutes. This accreditation takes into account not only the organization, diagnosis and therapeutic aspects of this molecular testing, but also what clinical research can be performed on what type of patient. The objective of the program is to guarantee that the patient has the most advanced treatment possibilities available, with a higher level of personalized analysis.

Accreditation is crucial for this type of research to ensure accuracy and reproducibility of results which, in my opinion, can be affected by at least three different factors. The first is the preclinical conditions of patients’ material. For example, with fixed and paraffin-embedded tissues, long ischemia times before fixation must be avoided, and sample acquisition and fixation should be performed with correct procedures in line with the recently developed CEN recommendations (3). The second aspect is the analytical methods used. These must be standardized and specific standard operating procedures should be followed, which include accurate internal and external quality control procedures. The third cause of irreproducible results is tissue and intratumor molecular heterogeneity, which is at the basis of clonal tumor evolution and acquired resistance to new therapies. This must be studied in depth, using tissues and “liquid biopsies” to define spatial and temporal development.

Understandably, this new approach to clinical research requires specialist facilities and is now viewed as an integrated activity in high-level clinical institutions. Not every hospital has direct access to these facilities though, and for this reason there is a real need for organized reference centres as an alternative for patients who need more sophisticated types of analysis and treatment.

Something else that needs to be very carefully considered is the bioethics of this type of approach. The fact is that we are using patient donor tissue or blood to support their own effective treatment, but also to perform clinical research, so this raises a number of bioethical issues. It’s very important that this matter is discussed together with patient associations and an agreement reached on how to deal with it.

Overall, I strongly believe that new organizational changes are needed in health institutions. Clinical research must be central in this new vision, which must be developed together with patient organizations. Our new approach must support the training and continuous development of clinical researchers so that they amass experience and expertise in applying the results of clinical research to a single patient. In order to do this, however, we will need to create national and even international networks of reference centers, so that this level of patient-centric care can be made available to everyone, irrespective of their location.