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Putting precision medicine on trial
by Cecilia Nardini
23 June 2013

There is no questioning that pharmacology has played an important part in the great advances of medical science in the last century. Dramatically effective and relatively cheap drugs, such as aspirin or antibiotics, have marked for many once very severe or even lethal diseases a conversion to treatable conditions. Such drugs are the so-called "blockbusters" and they have represented the pillars of pharmaceutical industry so far.

However, this model for discovering and developing new drugs is quite unrepresentative of the current state of affairs. Newly developed drugs are usually very expensive, being the result of an extensive research process, and typically provide only marginal gains in effectiveness as compared to existing products. This is not to say that new medicines are worse than old ones: Rather, the point is that some of the old medicines represented such major advances that they remain unrepeatable.

The change just described has however an impact on the standard of evidence. In order to provide sufficient confidence on the existence of a small effect, the test need involve a large population of patients. Indeed, in latter years, clinical trials in common conditions such as cardio-vascular diseases, respiratory conditions or diabetes are for the most part huge enterprises enrolling hundreds of patients in several hospitals, possibly across different countries.

Finding a sufficient number of patients willing to participate in a trial is becoming a serious issue, both for pharmaceutical sponsors and for public health authorities. Such recruitment problems have consequences in terms of trials that have to be discontinued. Furthermore, the increasing difficulties in recruitment in Western countries have lead to the ethically problematic practice to outsource trial conduction to developing countries, where ethical standards often cannot be properly warranted. Finally, the costs to set up and manage such large trials play a part in making the new medicines so expensive.

This setting may however be about to change. A novel concept is emerging at the interface of medicine and genomic sciences. The new frontier, often referred to as precision medicine, begins with the observation that response to drugs is not identical for everybody: Instead, different people metabolize pharmaceutical compounds differently and also the action of the drug on the disease mechanism can vary. Have you ever tried the painkiller your friend always takes when she has headache, and felt dizzy all day?

The individual response to a drug can however in certain cases be predicted on the basis of molecular markers, and we are becoming increasingly good at this. Hence, precision medicine consists in exploiting the available information about the molecular profile of the patients in order to tailor drug prescriptions accordingly. For instance, if a drug is known to be ineffective on patients that have a particular genetic variant, they will not be treated with it but using a different compound instead. This approach has several advantages. By taking into account the genetic makeup of the patient-drug interaction, the drug prescription will reduce the occurrence of adverse reactions. Furthermore, it can lead to a more efficient prescription practice by making sure that a drug is only administered to the patients who will actually benefit from it.

But is this --precision medicine-- ever going to be real? The European Science Foundation recently explored the possibilities offered by precision medicine report (Personalised Medicine for the European citizen - towards more precise medicine for the diagnosis, treatment and prevention of disease). But more importantly, precision medicine is becoming a clinical reality in the field of cancer treatment, where it goes under the name of targeted therapy. In the case of targeted oncology, the treatment is tailored to the molecular profile of the tumor rather than to the features of the patient.

An example of a targeted compound is the 'magic bullet' Gleevec, a competitive tyrosine-kinase used in the treatment of multiple cancers. Gleevec is dramatically effective in chronic myelogenous leukemia, because it targets the molecular abnormality causing the disease; however, it is totally useless against other forms of leukemia.

Precision drugs are expected to be effective only on a small segment of the original disease population. However, for this reason, they cannot be tested in the same way as old blockbusters, by measuring variations upon a large statistical population. If tested on a large, undifferentiated sample, the effect of these compounds upon the small subpopulation of responders will most likely go undetected. A whole new concept of clinical testing becomes necessary, whereby drugs are tested through a battery of small studies, each conducted upon a population of patients characterized through their genetic profile. Furthermore, in such trials, the clinical stage will have to be closely integrated with the laboratory, in a continuous flow of information from bedside to bench and back.

Precision medicine and targeted therapies, if they eventually will come to replace the traditional drug discovery pattern, will have a profound impact on our lives. But as they enter the medical field, they are undoubtedly revolutionizing our standards for evaluating medical evidence.

European School of Molecular Medicine
PhD Student
She is currently exploring some foundational issues in statistics and the way they impact the evidential and ethical aspects of randomized controlled drug trials.