The ethics and regulation of cell and tissue therapies in the UK

Published on August 31, 2015   44 min
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MARK LOWDELL: Hello, I'm Mark Lowdell. I'm the Director of Cell Therapy here at the Royal Free Hospital & UCL Medical School. And today I'm going to talk to you about the field of cell and tissue therapies, how they're regulated, and the impact that regulation has on the ethics.
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So I'm a Cell Therapist. I'm not a doctor here that treats cells. I'm a scientist that uses human cells and tissues to make medicines for tissue engineering, regenerative medicine, and treating cancer and immune deficiencies.
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Now these types of medicines are called Advance Therapy Medicinal Products. It's a clumsy term, and it was defined really in the first directive of 2001, 83, the Medicines Directive. And they consist of gene therapies, somatic cell therapies, and tissue engineered products for the purposes of regenerative medicine. Here are some examples: In the lower screen there you can see a decellularized human trachea that we were using to rebuild a trachea in a child. On the right of that there is a bioengineered nose made out of a biocompatible material. On the right hand side, a photograph from a different group using a similar sort of bio materials to produce an ear structure.
1:10
So how are these things regulated? Well, as I said, in 2001 the European Medicines Directive came in and for the first time it included human blood and blood products as a medical substance, and there was an implicit application that somatic cells from humans could be regulated as medicines. And they talked about them being substantially modified, but no definition of what substantial meant. In 2004, when the clinical trials directives was enacted, the same term, 'substantially modified somatic cells' arose. And so these for the first time could be a trial medicine, an Investigational Medicinal Product, or IMP. And this required the manufacturer full pharmaceutical standards of good manufacturing practice, GMP, plus a manufacturing authorization held by the manufacturer. And in Europe, a qualified person, the person with a status to legally release these, was very challenging at the time because qualified persons were pharmacists, and they didn't come from a cell therapy background. In 2006, tissues and cells were regulated by the European Union under the Tissues and Cells Directives. And these were enacted into UK law, meaning that tissues and cells that are used for transplantation purposes are regulated. And indeed those that are used as starting materials to make ATMPs are also regulated. In 2007 those regulations were published and we had to start applying them. And procurement of the starting material in the UK is regulated by the Human Tissue Authority. And in each member state there is a different regulator, and that requires a license to procure. The problem of nonsubstantial manipulation was finally defined with some examples of what nonsubstantial manipulation was. But no definition of what substantial manipulation is. And this still comes down to a decision by each member state. Within the ATMP regulations there was this inclusion of a strange clause called the Hospital Exemption Clause. Which allowed these medicinal products to be made one-off in a non-routine basis, no definition of non-routine, and for non-clinical trials. So these work for patients in extreme need, who needed treatment with a therapy that was not yet licensed and was not in clinical trial. And all of these regulations were then combined together in a rewriting of the European Medicines Directive in 2009 to produce the new Medicines Directive which includes these advanced therapy medicinal products. So a quick race through the regulation, if anybody is interested obviously those references are there, and one can struggle through them.
3:34
So since there are still a question, or there still is the question of advanced therapies being medicines, or non-medicinal. In other words, if they're not substantially modified, they're not a medicinal product. Plainly when one is developing one of these therapies you have to go through a decision tree to decide whether your product is medicinal, or whether it's non-medicinal. And these decisions are ultimately made by the competent authority for medicines in individual member states. In the UK that's the MHRA. And the European Medicines Agency can give you an opinion, but it's not binding. This is causing quite a lot of problem in terms of developing these products through Europe. And most of these products are still being developed in academic settings by academic investigators. And the resources to get these decisions made are actually not always readily available. So here's some examples of a decision process that one might go through. Is the product going to be used in a single, surgical procedure? Because that's one of the criteria that allows it to be non-medicinal. A good example of that historically has been bone marrow mononuclear cells. Stem cells from the bone marrow injected into coronary artery bypass grafts at the time of the graft in order to encourage and speed up the tissue regeneration of the damaged cardiac muscle. Now for many years that's been considered to be a non-medicinal process because it's a single product. It's autologous, it's the patient's own cells, and it's done within the same surgical procedure. However, recently, the European Medicines Agency decided that bone marrow mononuclear cells don't normally go to the coronary artery, and therefore this is non-homologous. So bone marrow mononuclear cells now in coronary artery bypass grafts are considered a medicine. That comes down to the second question, is the product going to be used homologously? What is non-homologous? Mainly it's been decided that bone marrow nuclear cells in the heart are non -homologous. But more recently, a decision has been made that adipose cells taken from abdominal adipose tissue, injected into a knee fat pad, of regeneration of the synovial fat pad, actually is non-homologous. There's no proof that the adipose cells that reside in your abdominal fat actually are the same adipose cells as those that are in your synovial fat pad. And, therefore, moving one from one site to another is non-homologous. And I suppose the most important decision that has to be made when assessing whether a product is medicinal or non-medicinal is whether what you do to it is 'substantial modification' or not. And the terminology used in the legislation is, is it 'substantially' modified immunologically, physiologically, or metabolically? See those are very challenging decisions to make at an individual level, but as a rule of thumb, if the cells are cultured outside the body for more than 24 hours in any way, shape, or form, that is being regulated at the moment across Europe as a substantial modification. And therefore, a fully compliant medicine in production.
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The ethics and regulation of cell and tissue therapies in the UK

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