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 [1].
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 [2].
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],[4],[5])
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 [6]. 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.
References
[1] 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
)
[2] 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
[5] http://pharmeuropa.edqm.eu/PharmeuropaArchives/
(EP general chapter 5.2.12)
[6] 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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