Assessing drug safety in human tissues — what are the barriers?

The drug development process is long and expensive. High attrition rates due to safety liabilities observed in the clinic, but that were not identified during nonclinical development, are a major contributor to the escalating costs and reduced productivity of the industry (Organs-on-chips at the frontiers of drug discovery. Nat. Rev. Drug Discov. 14, 248–260 (2015))1. This has called into question the utility of current preclinical safety-testing paradigms — which rely predominantly on animal models, including rodents, dogs and nonhuman primates — and led to demands for more-predictive tools. The development and use of human tissue-based assays provides an obvious alternative to the current approaches used to predict human pharmacological responses. However, despite this, very little drug development seems to be conducted using human tissues. We know from discussions with the UK Medicines and Healthcare Products Regulatory Agency (MHRA) that some companies do use these models for supporting internal early development decision-making processes, but this is on a relatively small scale and the data are rarely included in submissions to the international regulatory agencies. The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) and the MHRA are working together to evaluate the application and increase the uptake of human tissue-based approaches, to replace the use of animals and provide more-predictive tools to determine the safety of drugs entering clinical studies. We have convened an expert working group that comprises 25 individuals from a number of organizations (including academic organizations, companies and international regulators) to generate an evidence base to support these efforts (see Supplementary information S1 (table) for a list of members of the group). Our initial priority has been to assess the current use of human tissue through a survey of the international safety pharmacology community; however, the longer-term goal is the application of human tissue-based approaches to safety assessment in the broadest sense. Here, we present and discuss the results of this survey. Survey characteristics The working group developed the survey to gather information on general attitudes towards the use of human tissue-based approaches for generating safety data and record details of specific assays currently being used for safety assessment (see Supplementary information S2 (table) for the survey). The survey was distributed to the global safety-assessment community through various organizations, including the European Federation of Pharmaceutical Industries and Associations (EFPIA), the British Toxicology Society (BTS), the British Pharmacological Society (BPS) and EuroTox. The survey was completed by 27 individuals or companies who were primarily from large pharmaceutical companies (52%), with the remaining respondents divided equally between small pharmaceutical companies, biotechnology companies and academic institutions. The survey included information on 28 specific human-tissue assays currently being used for safety assessment. For the purpose of the survey, human tissue was broadly defined as any material derived from human sources, including organs, tissues, cells, biofluids and so on. Assays in which cells of human origin are used as vehicles for the introduction of channels were not included in the questionnaire.