By Fabio D'Agostino
Historically human cells have only been considered as the microscopic building blocks of human body and it was not until the late 1950s that Dr. E. Donnall Thomas demonstrated that bone marrow can be used to cure patients dying from blood cancers. Since then, researchers turned to cells (and stem cells) as the active pharmaceutical ingredient of the future.
In Europe, cell-based products in which cells have been either substantially manipulated or are not intended to be used for the same essential function(s) in the recipient and the donor are regulated as medicinal products under the legal framework of Advanced Therapy Medicinal Products (ATMPs). As ATMPs developers tried to comply with the same regulatory principles as for other medicinal products, EMA recognized the need for some flexibility given the complex nature of this advanced biologics. Although a certain degree of risk-based approach might have been adopted by developers in the last 20 years, EMA formally introduced a guideline in 2013 .
It is no longer the regulator but rather the developer who sets the extent of quality, nonclinical and clinical data which are necessary to submit the Market Authorization Application, given the risk profile generated for that product. Therefore, it can also be used as a strategy to justify any deviation from the technical requirements as defined in Directive 2009/120/EC. This approach was successfully applied for Holoclar®(Holostem Advanced Therapies, Italy), the first stem cell product which was granted a Marketing Authorization in the European Union in April 2015 .
Holoclar® is a transparent circular sheet of 300,000 to 1,200,000 viable autologous human corneal epithelial cells attached on a 2.2 cm diameter fibrin support in physiological transport medium. Although the manufacturer will have to provide additional post-marketing efficacy and safety data in order to confirm that the benefit-risk balance is positive, this MA represents an important landmark for developers of ATMPs. Other companies might follow in the next 12 months, such as GSK (who filed a MAA in May 2015 for their gene therapy drug - GSK2696273), Tigenix and Kiadis. It turns out that risk profile and risk mitigation are not actually just for investors but also for regulatory body and as for investors, they can tolerate risks as long as it is kept under control and a well-thought through mitigation plan is in place.
But where do the risks lie for ATMP developers? Here are some:
1) Quality of donor cells used as starting materials. These could be affected by high inter-donor variability and could potentially introduce tumorigenic or genetically altered cells into the product when sourcing the starting materials from patients concomitantly treated with other drugs.
2) Quality of raw materials. As many of the raw/ancillary materials currently available are not covered by pharmacopeia’s, developers should define the quality of raw materials they need for their products (more info can be found on PAS 157, USP Ancillary materials and EP chapter on Raw Materials for ATMPs ,,)
3) Impossible to remove/inactivate adventitious agents once in the product. Aseptic processing and rigorous control of donor cells used as starting material are paramount.
4) Limited stability (unless frozen) and limited amount of material available. For autologous products, this might limit the possibility for comprehensive batch release testing of the finish product (sterility, purity, identity, potency). Extensive process characterization, process validation and in process control data could supplement final product testing.
5) Paucity of relevant certified reference materials and the need to develop these in-house to ensure measurement reliability.
6) Increased cell manipulations can lead to genetic modifications and/or immunogenic response (also for autologous products)
The key word is product characterization. While regulatory authorities appreciate the technical and scientific differences between characterization of cell based drugs and other medicinal products, it is paramount to characterize the product in order to identify and confirm which quality attributes (QA) are critical to quality (CQA). This is also necessary to identify and confirm the critical process parameters (process characterization).
Arguably, two of the most discussed issues with product characterization are purity and potency. The former has to take into consideration the cells intended to elicit the therapeutic effect, all the other cells present into the products and also the remainders of cell debris, exosomes and reagents which might be present. For Holoclar®, the marketing authorization holder on the basis of clinical data justified that the active substance consists of a mixture of cells with an average of 3.5% of limbal stem cells as the main functional component. These were histochemically quantified by expression of the phenotypic marker p63-bright. Clonogenic transienty amplifying cells and terminally differentiated corneal epithelial cells are also present in the final product but these were not regarded as impurities but as supportive cell populations for the formation of the epithelial circular sheet structure. This is an example of cell-based product where purification steps are not necessary as both the active substance and supportive cell population act in concert to deliver the therapeutic effect. Even more complicated is perhaps the development of a potency assay which should be validated before entering pivotal clinical trials.
Suggested approach is to define a number of biological assays that can be correlated with clinical outcome as more data become available. It should be then possible to identify one or more markers which correlate with the biological function of the product (i.e. their mechanism of action), like the minimum amount of p63-bright cells for Holoclar®.
More examples can be found in Bravery at al.’s paper . Perhaps 20 or 30 years from now, we will be able to handle human cells like they were chemically defined entity and regulatory authorities will have issued “the magic to do list” to get an ATMP approved. Sadly, this is quite far from today’s reality. This should not mean that patients have to wait that long to get access to these therapies.
Fabio D’Agostino is a passionate life sciences professional with experience in both the medical device and biopharmaceutical industry. An active member of the PDA Cell and Gene Task Force, he has contributed to a number of conferences in the cell and gene therapy industries. He was also instrumental in the launch of the new journal: Cell and Gene Therapy Insights.
After graduating with Honours from the Polytechnic University of Turin (Italy) with a BSc and a Master’s in Biomedical Engineering, he started his career at LivaNova (formerly Sorin Group) before moving to Newcastle University to take an Engineering Doctorate in Biopharmaceutical Process Development. He currently holds a research position at the Institute of Genetic Medicine (Newcastle University) where he is responsible for the development of an innovative platform for modular tissue engineering.
 EMA/CAT/CPWP Guideline on the risk-based approach according to annex I, part IV of Directive 2001/83/EC applied to Advanced therapy medicinal products (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/03/WC500139748.pdf )
 Flory E, Gasparini P, Jekerle V et al. Regulatory viewpoints on the development of advanced stem cell-based medicinal products in light of the first EU-approved stem cell product. Cell Gene Therapy Insights 1(1), 109-127 (2015) www.dx.doi.org/10.18609/cgti.2015.010
 http://pharmeuropa.edqm.eu/PharmeuropaArchives/ (EP general chapter 5.2.12)
 Bravery, C. a., Carmen, J., Fong, T., Oprea, W., Hoogendoorn, K. H., Woda, J., … Van’T Hof, W. (2013). Potency assay development for cellular therapy products: An ISCT* review of the requirements and experiences in the industry. Cytotherapy, 15(1), 9–19. http://doi.org/10.1016/j.jcyt.2012.10.008
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