Millions of people suffer from neurodegenerative diseases such as Alzheimer’s or amyotrophic lateral sclerosis (ALS), and researchers around the world are diligently working on new treatments. Nevertheless, many of these diseases remain incurable and effective therapeutic approaches remain few and far between. This is mainly due to the fact that diseases of the nervous system are particularly complex and our understanding of them is still limited. But there are also shortcomings in preclinical research that could be avoided, as neurologist Ulrich Dirnagl and medical ethicist Daniel Strech from the BIH QUEST Center for Transforming Biomedical Research recently outlined in an essay produced together with an international team of authors.
Publication of negative results could reduce overestimation of therapeutic effects
“Many steps have to be taken before approval is gained for testing new therapeutics in a clinical study – from the initial analysis of active substances to experiments on living organisms and publication of the results,” explains Ulrich Dirnagl, founding director of the QUEST Center. “However, the data produced along this ‘preclinical chain’ are often not robust enough.” This can be due, for example, to the fact that the number of cases is too small, that results cannot be reproduced, or that negative results remain unpublished. An analysis of the literature on strokes, for example, shows that the high number of unpublished experiment results leads to an overestimation of at least 30 percent of the therapeutic effects of new treatment methods.
“We have a great responsibility”
The authors’ work makes reference to neurodegenerative diseases as this is a particularly problematic area, with extremely low success rates among early studies for new active substances or biological preparations. Ulrich Dirnagl takes the example of ALS – a fatal disease that progresses rapidly: “This is a disease where the patient really witnesses his or her own deterioration. Many participants in phase I trials attach great hope to every small improvement in their condition. In many cases, the burden of participating in a study is high, and the chances of success are usually low – for example, the lives of the patients may be extended by a few weeks, but they have a lower quality of life during this time. We have to take a very close look at the risks and burdens we expose the patients to by having them participate in such studies. We have a great responsibility.”
Do early clinical trials meet current ethical requirements?
Although there are guidelines in place for the design of preclinical studies (e.g., the ARRIVE guidelines published in 2010), the team of authors claims that these are largely ignored in practice. Furthermore, they claim that other statutory requirements, such as the European Medicines Agency (EMA) guidelines on how to design stroke studies, do not correspond to the current recommendations of experts in the field. They also highlight the questionable criteria used by the most important regulatory authority in the world – the Food and Drug Administration (FDA) in the United States: under its regulations, anyone who submits a study for initial tests on humans must demonstrate preclinical safety data, but not whether the therapeutics to be tested have proven to be effective in preliminary studies. “In general, the problems associated with preclinical research are so serious that we doubt whether early clinical trials meet current ethical requirements – such as the prior robust weighing up of benefit and harm,” says Daniel Strech, who has been Professor of Translational Bioethics at the QUEST Center since June 1, 2018. This Center has set itself the task of increasing the value and benefit of biomedical research at BIH and beyond. Among other things, QUEST promotes and develops enhanced quality management practices in research – for example, by providing researchers with electronic lab notebooks or offering further training courses on a variety of topics such as reproducibility. QUEST is particularly committed to promoting the publication of all study results in medical research, rather than a select few. The QUEST Center recognizes scientists at Charité and MDC who publish so-called “zero results.” These are studies in which the investigated hypothesis could not be proven, but which can nevertheless be useful – for example, to improve future experiments on the same research question.
An appeal to biomedical practitioners
“As medical practitioners, we need to be aware of the ethical implications of our research. This means not focusing solely on the next paper. We have to take translational research seriously and understand it as a chain that breaks wherever there is a weak link. The weakest link, as our work demonstrates, is often in the preclinical phase. We want to raise awareness of these shortcomings and their consequences – so that in the future, there will be more studies that cause less stress while offering greater chances of success for patient-oriented innovations,” says Ulrich Dirnagl.
Yarborough M, Bredenoord A, D'Abramo F, Joyce NC, Kimmelman J, Ogbogu U, Sena E, Strech D, Dirnagl U. The bench is closer to the bedside than we think: Uncovering the ethical ties between preclinical researchers in translational neuroscience and patients in clinical trials. PLoS Biol. 2018 June 6;16(6):e2006343. doi: 10.1371/journal.pbio.2006343.