Following our article 'Industry spotlight: regenerative medicine - part 1', published in the March edition of Bio Brief, in this second part we now look at a specific issue faced by the industry. Since part 1, the report of the Regenerative Medicine Expert Group (RMEG) has been published. This was called for by the House of Lords in its report published in July 2013. There are many issues dealt with in the Lords’ report and the RMEG report, so we have concentrated in this article on a single legal one. You can read our summary of the other issues here. In future articles we will try to tackle some of the other legal issues in more detail.
Overall, our view is that there is a way to go before RM businesses have a clear and easily understandable route to market with fairly predictable outcomes, but we think that the regulators are rallying around calls to make things easier.
When are human tissues or cells ATMPs?
The RMEG report suggested that clarification was required as to the boundaries of the Tissues and Cells Directive 2004/23/EC (TCD) and the Advanced Therapy Medicinal Products Regulation 1394/2007 (ATMPR).
The TCD applies to 'human tissues and cells' and 'manufactured products derived from human tissues and cells', where intended for use on or in a human recipient (including extracorporeal applications, such as topical creams).
The ATMPR applies to:
gene therapy medicinal products;
somatic cell therapy medicinal products; and
- tissue engineered product.
The areas of overlap between the TCD and the ATMPR relates to somatic cell therapy medicinal products and tissue engineered products, both of which, according to the ATMPR, may contain or consist of human cells or tissues that have been subject to substantial manipulation or are intended for adifferent essential function in the recipient and the donor. A 'substantial manipulation' must achieve relevant biological, physiological or structural alterations, and would not include any of the things listed in Annex 1 of the ATMPR (these are mainly physical acts like 'cutting').
Where the product in question does not contain or consist of any viable human cells and/or tissues, and does not act principally by pharmacological, immunological or metabolic action, it is not an ATMP. While cell 'viability' is generally well understood, the term 'principally' adds another level of complexity, although it is clear in the ATMPR that products containing viable cells or tissues are considered as having pharmacological, immunological or metabolic action as their principal mode of action.
Looking further at the overlap, where another directive applies, the TCD only applies in respect of donation, procurement and testing (not to processing, preservation, storage or distribution). Accordingly, where an ATMP contains human cells or tissues, the donation, procurement and testing of those cells or tissues must comply with the TCD. So, an RM product containing or consisting of human cells or tissues may be regulated: (a) under the TCD only; or (b) under the TCD (partly) and the ATMPR.
We see the following as potential areas of confusion:
Where certain things are harvested from cultured human cells or tissues, such as recombinant genetic material or modified antibodies, are those things 'manufactured products' for the purpose of the TCD?
When are autologous grafts and organs or parts of organs (which the ATMPR does not generally apply to) used for a different essential purpose?
When are alterations to tissues or cells 'substantial' but not 'relevant'?
Leafing through the legislation, there are undoubtedly many such areas of confusion and this is reflected in the European Medicines Agency’s (EMA) collection of responses on its recent reflection paper on ATMP classification (May 2015) – which runs to nearly 200 pages. The ATMPR does provide some clarifications, but fails (in our view) to set the tests out clearly. However, hopefully the CAT will be busy preparing further guidance to demonstrate the industry responses to its reflection paper.
The RMEG report also suggests that the industry is looking for help in understanding the requirements for clinical trials involving ATMPs. All such trials must be the subject of written authorisation before they are started. However, despite ATMP regulation being generally managed at the European level, that authorisation must come from the local competent authority (which is the Medicines and Healthcare Products Regulatory Authority in the UK). Putting politics aside, if the relevant experts have been drafted in at the European level, then perhaps the clinical trial application should go there too. This might result in efficiencies at the point when a marketing authorisation application is made to the EMA after a successful clinical trial.
It is also worth noting that, in respect of ATMP trial applications, the turnaround deadlines have been removed for such authorisations as well as the necessary research ethics committee opinions. This must be frustrating for RM businesses, which might experience significant delays, and at the very least indicates a general acceptance that this is complicated.
Written authorisation is also required for trials involving any medicinal product which contains genetically modified organisms (GMOs). RM products could contain GMOs or be made using them, so the application of GMO regulation is another topic that RM executives need to be well-versed in. The way that GMO regulation fits into the mix will be the subject of our next article.
Where to start…
Just looking at this single issue, there are huge complexities for RM businesses in first identifying what they are required to comply with and then what they need to do and who they need to deal with. A running theme of the Lords report, the RMEG report and other RM commentary is that the complexity of the legal framework and the plethora of applicable regulatory obligations puts a real strain on RM businesses (in terms of both management time and cost). However, the problem with a technology that merges many new technical and highly-regulated disciplines is that complexity is likely to be a necessary evil.
For a CEO of an aspirational RM SME, for example, the challenges must be daunting. In our view, even with the significant simplification that commentators are pushing for, the overall regulatory landscape for RM businesses is not going to be simple (at least not at any time soon). As such, RM businesses should factor into early funding rounds a pot of money to help develop or procure regulatory expertise so that the business can be designed around making compliance as easy as possible.