This new innovation could be a paradigm shift for clinical trials, but it’s not without issues
The digital transformation of the healthcare and life sciences sector is not restricted to software apps and potential uses of blockchain technology; rather, it covers the entire product development and commercialisation cycle. In addition to the potential for remote digitised human clinical trials, the development of “organs-on-chips” (OOC) could represent a significant shift in how trials are conducted.
OOC are living three dimensional cross-sections of major organs which mimic their structure and motion and replicate organ interfaces (such as the blood/brain barrier). Organs which have been replicated on a chip to date include the lungs, heart, kidneys, skin, arteries, female reproductive system and, even a ‘whole human body’. Recent developments have seen OOC embedded with electrodes which allow for the accu-rate and continuous monitoring of trans-epithelial electrical resistance (electrical activity of living cells) which allows scientists to gauge how cells are functioning and when they are damaged and healing.
The potential for this technology is significant. Not only might it replace animal testing, it may also provide a greater level of insight into the toxicology and efficacy of a study drug than animal studies currently do. Further, if OOCs are created using specific patient stem cells, this could further advance personalised medicine allowing physicians to curate treatments to maximise success before any medicine is administered to the patient.
While this offers a fascinating and exciting development, it presents certain legal and regulatory questions around how OOC technology will be treated by regulators and whether their use will, quickly, be accepted as reliably testing the safety and efficacy of a product such that it may proceed to a Phase I human trial. Indeed, such a change will require amendments to current laws: EU Directive 2001/83 requires animal testing before in-human testing. Similarly, detailed guidelines drawn up by the European Medicines Agency’s (EMA) scientific committees and the International Conference of Harmonisation (ICH), as well The World Medical Associations Ethical Principles for Medical Research Involving Human Subjects (the Helsinki Declaration), detail that new medicines should be tested on animals before they can be given to human volunteers or patients.
In order to be able to replace animal studies, OOC manufacturers will need to be able to demonstrate that OOCs provide comparable quality and usefulness of data for the purpose of safety evaluation as current animal studies. The FDA appears to be taking the lead on determining whether such a shift is practically possible: in 2017 it announced a research and development agreement with Emulate, to use OOCs in food safety testing. The FDA will begin conducting tests with ‘liver on a chip’ devices to determine whether they can be used to determine the effect of food, cosmetics and dietary supplements. But, even if OOC are capable of replacing animal testing, how will this reliance sit alongside the product liability risk of a defective OOC – something which is not an issue under the current model?
The current EU product liability regime derives from EU Directive 85/374/EEC (the ‘Directive’) and would apply to OOCs. While there is unlikely to be any direct exposure of patients to OOCs, a defective OOC could result in indirect harm to patients. For example, an inherently defective OOC or the misleading presentation of the reliability of data generated by an OOC could lead to patients being prescribed ineffective, inappropriate or incorrectly tested medicinal products which may cause significant injury to patients. This may be further complicated in the context of designing personalised medicines regimes, when the responsibilities and liability of pharmaceutical manufacturers and physicians may also apply.
Equally, OOC manufacturers might be subject to actions by pharmaceutical manufacturers who rely on data generated by a defective OOC in the development of their medicinal products. In the event of a defective OOC, medicinal products may not be tested correctly resulting in incorrect data which could result in a product appearing to be unsuccessful when it is in fact successful and vice versa. This alone could give rise to substantial damages claims e.g. damages for lost opportunity or profit and damages from personal injury claims by patients administered the resulting medicinal product.
In each case, the difficulty for patients and pharmaceutical companies is likely to be being able to: (i) demonstrate that the relevant OOC (or the data it generates) is in fact defective; and (ii) that such defect caused the relevant harm e.g. the prescription of ineffective medicines or the development (or not) of a particular medicine with a particular composition, dosing regime and label.
The European Commission has recently conducted an evaluation of the Directive and its relevance to current technology as a result of widespread concerns as to whether the Directive remains fit for purpose. The European Commission intends to issue guidance on the Directive next year which, in particular, should include its response to whether the definition of “defect” is broad enough to encompass current and future technical advances. This guidance may also address the treatment of medical devices and medicinal products, which the European Commission has already indicated might be better excluded from the scope of the Directive given the difficulties faced in demonstrating a causal link between the defective product and the damage suffered.
The use of OOCs in product development and delivery presents exciting possibilities for the healthcare and life sciences industry: improving patient outcomes, improving animal welfare and potential cost savings for drug discovery. However, there remains a long way to go before the full benefits of this technology can be realised. A sufficient number of jurisdictions will need to accept the equivalence of OOC studies for animal studies before material benefits to animal welfare and cost savings can be demonstrated which, given the current regulatory position, may take considerable time. If such technology is adopted in this way, OOC manufacturers and other industry stakeholders will need to be mindful of the resulting liability risks and challenging legal regime in which these liabilities might be assessed.
Lydia Torne is a managing associate and Boris Handorn is a partner, both at Simmons & Simmons