“Lost in the Maze? Navigating Evidence and Ethics in Translational Neuroscience”: Herrenhausen Conference, Hannover, Germany 2018

By Sarah McCann

‘It is a veritable desert as far as favourable outcomes in neurological research are concerned’ –Jonathan Kimmelman, bioethicist

The reasons behind our failure to translate preclinical efficacy to clinical benefit, and the ethical challenges associated with early phase clinical trials of these treatments were dissected and debated at Herrenhausen Palace in February.

Thanks to the conference organisers and the Volkswagen Foundation, I had the opportunity to participate in this conference which brought together approximately 200 attendees including patients, patient advocates, carers, clinicians, preclinical and clinical researchers, research ethicists, and publishers.

With the publication last month of a PLOS Biology perspective paper authored by the organising committee, I reflected on my lasting impressions of this unique conference. My perspective is that of a preclinical researcher who has worked with animal models and more recently in metaresearch, diagnosing obstacles to translation.

So, are we lost in the maze? After opening sessions exploring the breadth of the problems we face, and seemingly without a clear way forward, my response was an emphatic ‘Yes’.

Weaknesses in preclinical research

Good evidence is the basis of correct action and we need increased certainty in our preclinical evidence to ensure robust foundations for clinical trials.

As a researcher in the field, many of the themes were familiar: preclinical evidence has poor validity as experiments are often not designed, conducted, or reported with sufficient rigour; animal models are not necessarily modelling what we think they are; exploratory research which may not be properly designed or powered is sold as confirmatory, hypothesis-driven research, muddying the research waters further.

How can we improve?

Keynote speaker, John Ioannidis, was asked if we need “a Harvey Weinstein-style scandal to improve the situation?” His response: scandals can be effective but in science, questionable research practices and cutting corners are more prevalent issues than newsworthy scandals.

A range of possible improvements were discussed but underpinning most seemed to be the idea that nothing will change unless our reward structure changes and more responsible metrics are adopted. Reward (through funding, recognition, promotion) should be based on metrics including research quality, transparency, replication, and team science. We need to educate scientists on robust experimental and statistical methods, and open science.

Ethical implications

Less familiar to me were the conversations around research ethics and patient viewpoints. Scientifically unsound preclinical research is not only ethically unsound in itself; but also creates ethical concerns where it feeds into patient-based trials.This seemingly obvious facet of biomedical research can be overlooked in the sometimes blinkered environment of a laboratory. The intersection of preclinical research with ethics, and exposure to the lives and ideas of those living with neurological diseases – through case studies, and patients and carers themselves – was extraordinary and provided a new perspective to my everyday research. Having exhausted all other treatment options, early phase neurological drug development trials can give hope to patients. However, there is a burden of risk in these trials that many participants, often subject to misunderstandings or unrealistic optimism, fail to appreciate. In Phase I trials, there is little chance of therapeutic benefit, almost certainty of some toxicity and discomfort, and the risk of mortality.

Despite knowing that most drugs tested in animals fail to translate to clinical benefit, I had not considered in depth the impact these trials have on patients and the people close to them. Many of the ethical concerns associated with early phase clinical trials are closely tied to preclinical research. Investigator brochures, which summarise the body of evidence relating to a drug under development, often reference preclinical evidence with no indication of the quality of the evidence or how trustworthy it might be. How can a patient give ‘informed consent’ to participate in a trial if the risks or benefit they may be exposed to are unclear? Clinical trials are launched by sponsors, and regulators cannot be counted upon to vet the preclinical information they provide to participants. So where does the responsibility for ensuring that patients are fully informed lie?

It was also interesting to hear that preclinical and clinical researchers do not always address the questions seen as most important by people living with neurological conditions and their carers: a disconnect can exist between researchers’ aims and patient needs.

Improving the validity of preclinical research is just one aspect of addressing these and other ethical concerns. There were a variety of discussions where I realised additional ways that my research could have greater impact. For example, engaging trial participants and the wider community with preclinical research, as discussed in detail by Katherine Cowan, allows them a greater appreciation of the research process. This may help to manage patient expectations regarding clinical trials, and better align research priorities with patient needs. Educating lay audiences on research methods and critical appraisal will help in developing strategies to ensure adequate informed consent, and indeed have wider benefits in allowing people to make informed health decisions.

Take home messages

The conference gave me an appreciation that shaky preclinical data can have impacts far beyond an inability to reproduce findings. As researchers, we provide hope to patients and need to be cognisant of our responsibility to contribute scientifically and ethically sound, high quality biomedical evidence. It also gave me a broader perspective of the research cycle and the benefits of input diversity, the exchange of ideas between various stakeholders, and the importance of a cohesive approach.

During the conference, coming to any sort of agreement on a way forward seemed highly unlikely. The issues identified are complex and not easy to address; there will be no quick fix. But I left feeling hopeful that with people dedicated to affecting change we can navigate our way towards better research and better outcomes for patients.

Sarah McCann is a Marie Skłodowska Curie Research Fellow at the Centre for Clinical Brain Sciences, University of Edinburgh.

Conflicts of interest: Sarah McCann received a travel grant from the Volkswagen Foundation to attend the Herrenhausen conference.

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