Dr. med. habil. Matthias Rother: Patient-centred clinical development = translational research

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Over the past few years, translational re­­search has become a popular catchword, which is used in the competition for research funds. This field of research has made it its business to rapidly ad­­vance basic research findings to make them directly available to people. This means that newly developed medicines and medical products are to be transferred from preclinical development to clinical practice and approved for application in a short period of time.

These well-meant intentions, however, are contradicted by empirical trends which prove that despite higher expenditure – the average cost of bringing a new drug to market has increased from some 100 million euros in the 1980s to an esti­mat­­­ed amount of 800 million euros today – the number of new, innovative treatments made available to patients is rather on the decline. For instance, the annual amount of new agents cleared for marketing by the US Food and Drug Administration (FDA) has dropped from 36 to 18 since 2004.

There are, no doubt, plenty of reasons for this development, but two of them seem to us particularly striking. In the first place, the amount of bureaucracy and administration associated with clin­­ical trials has increased steadily, partly due to the growing number of legal re­­quirements. In addition, the critical ques­­tion has to be raised whether it is not actually the quality in conducting such trials that has deteriorated, irrespective of formal requirements. This assumption is backed up by the fact that, although the number of clinical trials has multiplied over the last 20 years, these efforts have not resulted in a higher number of ap­­provals, as was said before.

The fact that in the 1980s, approval stud­­ies with sample sizes of less than 100 pa­­tients per therapy group produced clear, statistically significant results leading to approval also points to a decline in qual­­ity. The effectiveness of those medicines was later confirmed in clinical practice. In contrast, nowadays approval studies carried out for similar indications and involving several hundred or thousand patients per therapy group, simply fail. To illustrate this, let us take a look at pain-relieving drugs (analgesics) such as Di­­clofenac or Naproxen.

Today, the effectiveness of both medicines is an undisputed fact, which is why they are often used as reference drugs in the testing of new agents.
Despite their established clinical effectiveness, which was previously verified even in very small-scale studies, the pain-relieving effect can sometimes not be verified in current large trials with hundreds of pa­­tients. The question is: How can this be ex­­plained?

We are convinced that, on the one hand, this is due to the changed conditions under which the parties involved in drug development work today (see picture). 20 years ago, there used to be direct communication between the pharmacol­­ogist or head of development depart­­ment who had designed a product con­­cept and the investigator who tested that concept on patients. Today, a variety of structures lie in between. It must be assumed that there are “Chinese whispers effects”, which means that the pharmacologist’s intentions are not always correctly transmitted to the in­­vestigator. On the other hand, findings of the investigator or patient that go beyond the information obtained from standard patient questionnaires are hardly ever communicated to the person in charge of product development. But it was this valuable information on details in particular which in the past lead to new insights about test compounds or, where appropriate, to im­­provements in the study protocol, re­­sul­­t­ing in a better quality of the study out­­come. It can also be assumed that more and more clinical studies are carried out by doctors in the early stages of their clinical training or with little experience in their field of expertise. Otherwise it would be impossible to explain the some­­times huge differences between the re­­sults of participating test centres. In a large study, in which the author was also involved, it was possible to distinguish clearly and with statistical significance between centres that were able to confirm the pain-relieving effect of Naproxen on knee osteoarthritis, and others which were not.

I do not wish to join in the lament that “everything was better in the past”. What matters more is the question of how to respond to the changed environment. That is why conducting translational re­­search remains all the more important. Conclusion: The simplest form of trans­lational research consists in having clin­­ical research in patients carried out by doctors who have both in-depth experience of the development processes of medicines or medical products and spe­­cialist know-how in patient care. In ad­­­­dition, development programmes should be planned with the participation of doc­­tors who have been personally involved in patient care during clinical trials.

Passfoto-MR-juli2009The author is the Clinical Operations Di­­rector of the company X-pert Med GmbH, based in Gräfelfing. Dr Matthias Rother studied medicine at the University of Jena, where he also became a professor of neuro-pathophysiology. He was active at the Max Planck Institute for Neurolog­ical Research in Cologne and for several years worked for the Hoechst group in the US.