The Ins and Outs of Clinical Trials
by Andrew Webster and Ruchi Higham
Clinical trials are of central importance in the development of any field of medicine, used to test whether a new medicine – drug, device or cell therapy for example – is safe, effective and meets clinical needs. Regenerative medicine, however, poses some particular challenges for trial design given its use of live cells rather than, for example, chemical compounds seen in the pharmaceutical approach. Here, based on Ruchi Higham’s PhD research at York, work which was linked to the wider project, she outlines some of the main issues this raises.
Unlike many drugs, cell therapies are often complex interventions with multiple, interconnecting uncertainties. Many of these uncertainties can only be resolved by actual use in the clinic. Testing in animals is the usual way of assessing the safety and toxicity of a drug before using it in humans, but this is not very accurate for cell therapies, because the cells will respond differently when introduced into humans. Determining dose levels, for example, based on extrapolation from animal studies is likely to be of limited use. Moreover, dose requirements might change over time: for example, a patient with Alzheimer’s today may have to have a higher dosage in the future. And the mode of delivery is more complicated than that found with drugs: developing the best delivery – such as the infusion or implantation of cells - may take a number of iterations.
More generally, there is no such thing as a ‘typical’ cell therapy trial–the landscape is very fragmented, and most trialists identify more closely with their clinical area than with ‘cell therapy’ or ‘regenerative medicine’. Beyond the specific clinical difficulties using a conventional trials design, the main challenges experienced when running a trial are largely caused by financial constraints, the logistics of working with cells, the length of time required to undertake trials and coordinating the different disciplines involved.
The principal developments in the field relating to trials design will be shaped by new regulatory and legislative steps being taken at the EU level. Three aspects of EU policy are of most relevance to cell therapy trials: the Clinical Trials Directive, the ATMP regulations and the role of the European Medicines Agency. The impact of Brexit here is uncertain: on the one hand, leaving the EU might be seen as providing an opportunity to adapt and improve the trials design process and address some of the challenges posed for cell therapies, yet, at the same time, UK researchers and clinicians will want to ensure that their work is regarded as robust as elsewhere, and so meet the highest regulatory standards.
The main challenges relating to trials in this area relate to both the need to re-think how best to design trials that are appropriate to the regenerative medicine domain, how these would in turn relates to the changing world of regulation of advanced therapies, and what impact new clinical trials regulation from Europe will have, for example in regard to new guidance on trials awaited from the European Medicines Agency.
Key REGenableMED insights:
Overall, the research indicates that a novel approach to trialing in the regenerative medicine field is required, and various recommendations can be made, as described below. In broad terms, a progressive approach to licensing which would ease the financial burden on companies whilst clinical testing is ongoing would be helpful, and secondly, better use of the safety, efficacy and mode of action data generated by small-scale clinical testing within hospitals would provide extremely useful complementary evidence to the formal trials process. The role of patient agency is crucial in the trials process, and the research demonstrates a significant tension in cell therapy trials between protecting patients from undue risk whilst also allowing them to make their own decisions about the risks they are prepared to take. Cell therapies offer specific challenges in this area because the complexity of the science makes informed consent particularly difficult.