Regulator Q&A: Human tissue-based models in medicine development

M Beharry MHRA, Sonja Beken FAMHP, Susanne Brendler Schwaab BfArM, A Holmes NC3Rs, S Jackson NC3Rs, D Jones MHRA, Tiina Palomaki Fimea.

In association with the NC3Rs Working Group on Human Tissue in Safety Pharmacology

Version 1.1 - November 2017

The aim of this Q&A document is to provide clarification on the views of the agencies involved in the regulatory acceptance of the use of human tissue models in support of medicines development. This document has been prepared following an NC3Rs workshop and in collaboration with members of the NC3Rs/MHRA Human Tissue in Safety Assessment working group. Endorsement of the document by the individuals listed is not an indication that the agency they are working for has ratified this document, despite that the respective agencies support the principles of 3Rs in general.

Question 1. Can data generated from human tissues models be used in the evaluation of new medicinal products?

 

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.

Question 2. Can data generated from human tissues models be used in the safety evaluation of new medicinal products?

 

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].

Question 3. Can data generated from unvalidated human tissues models be used in the safety evaluation of new medicinal products?

 

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.

Question 4. What sample meta-data would need to be included?

 

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.

Question 5. Can data generated from non-GLP compliant human tissue models be used in support of the evaluation of new medicinal products?

 

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.

Question 6. Where can scientific guidance be found regarding a new human tissue model?

 

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:

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

Question 7. Are there any validated human tissue models available that can be used in support of PD or pivotal safety studies?

 

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

Question 8. Will there ever be a time that data generated from human tissues could replace traditional toxicology safety endpoints?

 

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.

Question 9. What are the opportunities for engaging with the MHRA on the development and application of new models?

 

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

[1] Megit S. Immunocore pioneers new safety studies. In MedNous 2011; 5: 14–15