As a regulatory lawyer long-steeped in the world of stem cells and regenerative medicine, I’m bound to latch onto the title of a recent Nature piece with particular interest. Cells or drugs? It’s a great question from a regulatory point of view.

You can’t place any medicine on the market, whether it’s a small molecule, a gene, or the fanciest of engineered cells, without a marketing authorisation. However, getting an MA can be pretty demanding, and especially when it comes to an advanced therapy product (ATMP) such as a population of cells. Avoiding cells has some obvious attractions.

The article reminds us that cell therapy is less about cells than their fate. Of course, manufacturers of such cells are obsessively concerned about their fate from a product point of view.

However, the bigger question is about what happens to the cells once they’re implanted. At least as important, what happens to the cells that were already at the implant site? The more we learn about how damaged tissues behave and what implanted cells do in their new home, the more it comes down to an understanding of the “conversation” between cells that determines their phenotype. If we assume that the conversation is mediated by molecules, then we only need cells because we don’t yet know what those molecules are or because cells happen to be the best delivery device for them. If the cellular conversation is about growing new cells to replace those lost to ischaemia, for example, the proliferation of any cardiomyocytes surviving implantation may be of less importance than getting the wound site to grow new cardiomyocytes.

An alternative approach would be to mimic that molecular environment to administer well-characterised molecules at known doses. They wouldn’t be ATMPs at all, so the extra ATMP burdens that fall on such products under regulations such as the ATMP Regulation would not apply; just those for a conventional biological medicinal products.

Regulatory reflection

Anyone familiar with the manufacturing requirements for somatic cell or tissue engineered products will know that the logistical and quality burdens on those seeking an MA for an ATMP far surpass even those for non-biological medicinal products. It is perfectly true that, under the EU’s 2007 Advanced Therapy Medicinal Products (ATMP) Regulation there are only three varieties of ATMP: medicinal products comprising somatic cells or genes, and cells which have been substantially manipulated or used to fulfil a different function in the recipient than in the donor.

But why shouldn’t an advanced therapy be delivered the old-fashioned way, as a drug?

The European Commission is reviewing EU blood, cell and tissue (BCT) quality and safety regulation (more on this soon), but has excluded the ATMP Regulation from its review. The Nature article does not touch upon regulation, but to me it suggests another reason for revisiting the ATMP Regulation in the light of changes in scientific understanding. The problem is that, although the ATMP Regulation shoe-horned cell and gene medicinal products into the well-worn boot of European medicines regulation, the foot doesn’t entirely fit.

If you recall the heady days of the early 2000s in which the Regulation was developed, the future was one in which bags of embryonically-derived cells for fixing hearts and spines were distributed around the world like blister packs of ibuprofen. The future unfolded rather differently. Within months of the Regulation coming into effect, an invention for inducing pluripotent stem cell induction was published, reducing the necessity for embryonic cells (with the development of stem-cell based embryo models making even embryos unnecessary). More fundamentally, the future turned out to be dominated, not by packages of cells derived from other peoples or embryos, but by the use of the patient’s own cells; “autologous” cells.

However, the word “autologous” doesn’t appear in the ATMP Regulation at all. One perfectly logical reason for their non-appearance is that it’s questionable as to whether a product intended solely for one person can be truly said to be placed on a market at all. If so, it’s at least odd to talk about authorising such a product to be placed on one. Sure, we legal our way around this so that autologous products do come bearing MAs, but this regulatory chafing of the cellular heel implies that the paradigm is wonky. The EU’s BCT regulations already address quality and safety framework for cells, so perhaps the autologous cell therapy market is better regulated as a service than on the basis of a marketable product?

You get another idea about how awkwardly cell products fit into the regime for marketing medicines when you ask questions such as, “what is the mechanism of action?” and “what is the dose?” Again, we can get around irritating questions of this sort, but we should certainly pause for thought, and the Nature piece rather sharpens our appreciation.

Javaria Tehzeeb, author of a 2019 literature review on stem cell heart treatments that’s cited in the Nature piece, wonders how things are likely to pan out. Perhaps stem-cell therapies will be approved first, but then be overtaken by drugs once the science has caught up? “When we get to the end of the line with molecules, then maybe we can say stem cells are a thing of the past,” says Tehzeeb. The manufacturing logistics and regulatory path to market would certainly be more straightforward, and there would be real control over the nature and amount of substances applied, in contrast to the informed-wing-and-prayer approach of cell injection. But we’re not in that future yet. As Tehzeeb says, “until then, we should continue to pursue their potential.”

As in life science, so in life science regulation it’s a work in progress…