Human Tissue for Safety Pharmacology Regulator Q&A: Human tissue-based models in medicine development

Yes, the use of human tissue data in support of regulatory submissions is acceptable to inform and investigate the pharmacodynamics (PD) of medicines in early phase development.

At the present time there are no validated human tissue models that can replace the pivotal safety study endpoints that are required in the safety evaluation of new medicinal products; however data from unvalidated human tissue models can inform and add to information gained from these pivotal safety studies (see below), and in some unique cases have replaced it [1].

Yes, it is acceptable to use data from unvalidated models to support or inform non-clinical pivotal safety studies. If such data are to be included in regulatory submissions, the context in which these data are being used should be made clear (i.e. supportive). In addition, a discussion of how the model is characterised, current validation processes and what mechanisms are that are being investigated must also be provided. Data summaries and a critical assessment of the strengths and limitations of the model/data would need to be included and the original study reports and raw data included or made available, on request. Most importantly the relevance to the clinical situation must be made clear and any divergent results from what is expected should be explained.

The meta-data required in relation to the tissue itself would depend on the model in question. Details of the samples in relation to age, sex, ethnicity, lifestyle (if available), and possibly cause of death and/or comorbidities would be required. Importantly, information around the viability, quality, source and integrity of the samples would also need to be provided. There may be other requirements if diseased tissues are used, however, these would be specific to the model in question. This can be discussed with the MHRA in the first instance.

For pharmacodynamic (PD) studies there are currently no requirements for such assays to comply with GLP. At the present time data generated from human tissues, studies could not be used in isolation to support clinical safety. However non-GLP human tissue data can support and inform these pivotal safety studies.

There are Europe wide regulatory initiatives that provide a platform for the development of such models.  The Committee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary Use (CVMP) guideline on regulatory acceptance of 3Rs testing approaches (currently open for consultation) describes the process for submission and evaluation of a proposal for regulatory acceptance of 3Rs testing approaches (such as new human tissue models) for use in the development and quality control during production of human and veterinary medicinal products. It also presents the scientific and technical criteria for validation of 3Rs testing approaches and describes pathways for regulatory acceptance of 3Rs testing approaches.

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500174977.pdf

There are also a number of international initiatives and organisations involved in the development, validation and dissemination of technologies, including:

• European Directorate for the Quality of Medicines
• European Partnership for Alternative Approaches to Animal Testing
• European Union Reference Laboratory for Alternatives to Animal Testing
• Interagency Coordinating Committee on the Validation of Alternative Methods
• Japanese Centre for the Validation of Alternative Methods
• The Organisation for Economic Co-operation and Development
• European Medicines Agency Innovation Task Force
• National centre for the replacement, refinement and reduction of animals in research

Both national and European (via European Medicines Agency (EMA)) scientific advice can also be requested.

• EMA: http://www.ema.europa.eu/ema/index.jsp%3Fcurl%3Dpages/regulation/general/general_content_000049.jsp
• MHRA: https://www.gov.uk/guidance/medicines-get-scientific-advice-from-mhra

At the present time there are no validated human tissue models, however, there are a number of cardiovascular models that are in development.

As with any new method, as more data becomes available, confidence grows and these data are included in increasing numbers of regulatory submissions as supporting evidence. The methods become validated and accepted over time through this process. Eventually, when there is enough data to show that they can reliably and fully demonstrate safety and the data used can be extrapolated to the clinical setting, they will start to replace the traditional in vivo endpoints.

You can ask for scientific advice from the Medicines and Healthcare products Regulatory Agency (MHRA) at any stage of the initial development of your technology. The MHRA operates a ‘safe harbour’ approach such that all discussions take place in an environment to allow free exploration of the technical data and/or development plan in a confidential manner and without a commitment from either side.

The MHRA Innovation Office helps organisations that are developing innovative medicines, medical devices, using novel manufacturing processes or other novel technologies to navigate the regulatory processes so they can progress their products or technologies.

https://www.gov.uk/government/groups/mhra-innovation-office