Advanced therapy medicinal products (ATMPs) include gene
therapy, somatic cell therapy and tissue engineered products. They are
regulated under EC/1394/2007 within the European Union (EU) in order to ensure
that products are fit for their intended clinical application (1). Academic
Good Manufacturing Practice (GMP) facilities are major contributors in the
development of ATMPs, with many products being produced for autologous use. A
recent article by Pearce et al describes the implementation of the European
Commission regulation across the EU and highlights implementation discrepancies
within member states (2). This review will discuss how the regulations impact
on the development of ATMPs and how autologous products pose particular
problems.
Autologous ATMPs and Commercialisation
Predominant activity in the early phase of cell therapy
development has focused on individualised treatments – often of autologous
products or allogeneic cells – prescribed to single patients. This
patient-specific approach does not immediately lend itself to
commercialisation, yet their categorisation as medicinal products means that
manufacturing and regulatory pathways designed to regulate companies that
manufacture traditional pharmaceuticals must be navigated. Cell therapies for
human use are therefore governed by EU Directives on GMP – the part of quality
assurance which ensures products are consistently produced and controlled in
accordance with the quality standards appropriate to their intended use (3,4).
Many of the Medicines and Healthcare Products Regulatory
Agency (MHRA) licensed GMP cell therapy manufacturing laboratories in the UK are based
within major academic institutions and teaching hospitals (5). These institutions
have invested in necessary infrastructure following the EU directives
regulating the manufacture of cellular therapies. The ATMP regulations
specifically provide guidelines for cell therapies, alongside gene therapy and
tissue engineered products (1). They relate to cell therapy products of
substantially manipulated cells which, by reference to the EU Medicines
Directive, must be manufactured by an industrial process and be placed in an EU
member state market (4).
Certain processes, such as centrifugation, cell separation
and purification, are not regarded as substantial manipulation and do not
invoke ATMP classification. In these cases, the product is not an ATMP and the
EU Tissues and Cells Directive applies – for example, in haematopoietic stem
cell transplantation or allogeneic pancreatic islet cell transplantation (6).
However, in some cases substantial manipulation is not required for ATMP
classification if the intended use differs from the original function of the
cells, such as in non-homologous use. This can be seen in autologous bone
marrow-derived progenitor cells intended for the treatment of patients with
myocardial infarction (7).
Universities and hospitals have been able to meet the
initial costs of establishing and staffing the facilities required for GMP cell
therapy manufacture, whereas some commercial operations have struggled to
achieve cost reimbursement (8).
Many cell therapy products are considered to be advanced
therapy investigational medicinal products (ATIMPs) as they fulfil the criteria
requiring a clinical trial. Securing and maintaining a manufacturing licence for
ATIMPs is a significant task and is dependent upon demonstrating to competent
authorities – such as the MHRA – that a facility meets the structural and
design specifications making it fit for purpose, as well as demonstrating a
Pharmaceutical Quality System compliant with GMP (9,10).
Under the requirements of the manufacturing authorisation
for investigational medicinal products (IMP), each batch of a medicinal product
must be released by a Qualified Person who must assess release criteria and
adherence to GMP standards. In the case of the autologous product, this must be
performed for each treatment, which is, by definition, a separate production
batch each time a patient is treated.
The regulations require a rigidly controlled environment
which is suited to mass production by high throughput or automated
pharmaceutical processes, manufacturing many doses per batch of a particular
medicinal product. Whether this is entirely applicable for a single-patient,
single-dose product for immediate administration with different risk profiles
is debatable.
In academic institutions, the availability of infrastructure
and production skills often grows out of academic research interests that are
locally driven by the clinical research teams and funded initially by Research
Council grant awards. These teams seek to address unmet clinical needs, advance
research, knowledge and understanding of particular diseases, and are not
driven by profitability of downstream commercialised products. Examples include
the Medical Research Council-funded autologous limbal stem cell (ALSC) project
which is a clinical trial developed from academic research within the
Department for Opthalmology in Newcastle, and in the production of tolerogenic
dendritic cells funded by Arthritis Research UK (see Figure 1) (11,12).
The ALSC project can be taken as a case study in point. The
programme, published by the investigators in Newcastle, describes the
manufacture of a small cell population that is used to recapitulate limbal stem
cells in eyes traumatised by chemical or abrasive injury (see Figure 2) (11).
As an autologous product, the original tissue comes from the same patient who
then receives the final product, but it is classified as an ATMP since the
cells are considered to be substantially modified and, hence, require
manufacturing in an MHRA-approved facility. Prior to approval as a marketed
ATMP with marketing authorisation (MA) – a permit to make, market and sell a
medicine with exclusivity to supply that medicine for 10 years – the ALSC would
be involved in clinical trials and assessed by the European Medicines Agency
(EMA), which regulates these products for patient safety, efficacy and quality
(4).
There has been much debate about the volume of data needed
by the EMA to secure an MA for an ATMP (13). It is perhaps revealing that there
are no autologous ATMPs currently awarded an MA. Furthermore, there has been
little research into the advantages of possessing an MA for the holder, the
manufacturer, or the patient (in the context of safety of the autologous product).
At present, any such products marketed as ATMPs – and after trials as IMPs –
but manufactured for a single specific patient, will be subject to the
requirements for traditional pharmaceuticals, such as validated production
processes within regulated premises, and managed under a Performance Qualification
Standard and a regimen of regulatory inspection.
The post-marketing pharmacovigilance process for an ATMP is
similarly demanding, requiring continuous report assessments from various
sources and the engagement of a specialist Qualified Person for
Pharmacovigilance. This is despite the fact that each cell product is
manufactured for one specific and autologous patient – he or she receives their
own cells.
As specific cell therapies are developed, their
compatibility with the regulatory framework in place will be increasingly
tested. Autologous products in particular pose a challenge to business models,
as each batch of a product can only treat one patient. The EU Medicines
Directive encourages medicine manufacturers to possess an MA. However, a
Europe-wide MA – enabling an institution to protect their autologous cell
therapy process – could be considered excessive if the geographical region that
the MA holder can supply is restricted to the local vicinity of the
institution. An example of this would be if product quality has a very short
life outside of the GMP manufacturing facility, or if the product is in a form
that cannot be readily transported without compromising the viability of the
cells.
The Directive, in certain circumstances, requires cell
therapy products to be regulated as ATMPs and advocates manufacture under an
MA, but it is clear that there may be circumstances where this classification
could prevent the development of specific and individualised therapies offering
patients relief from suffering.
An alternative to obtaining an MA for an autologous product
is manufacturing under the Hospitals Exemption (or the Specials Manufacturing
legislation in the UK,
authorised by Article 5(1) of Directive 2001/83/EC) (14). This exemption
permits the manufacture of unlicensed ATMPs in a hospital under the exclusive
guidance of a responsible physician. Indeed, in the latest feedback to the EU
from October 2012, 18 such authorisations had been granted in the UK
(15).
There is scope for the EMA to interpret the legislation to
bring the autologous product outside of the ATMP regulations, with regards to
negating the need for an MA, but still remaining within the technical and
quality requirements. The ATMP regulations only apply to cell products subject
to substantial manipulation during production and manufacturing by an
industrial process, or by a method involving an industrial process. The
manipulation and culture of cells in a laboratory for the treatment of one
autologous patient could be defined as lacking any ‘industrial process’ and,
consequently, the EMA could rule that an MA is not required for this class of
products.
The interpretation of the ATMP regulations is devolved to
the competent authorities of each EU member state. Specific guidance indicating
that the ATMP regulations will not apply would ensure that centres developing
these processes do not need to proceed with the considerable task and cost of
seeking an MA to place the product on the market. However, they could still
market their services and seek cost recovery for each patient treated. We do
not advocate de-regulation of ATMP’s but this would simply provide an alternative
pathway to commercialisation.
The EMA could designate that the Hospital Exemption is the
expected route for autologous ATMPs and provide specific standards required, or
consider guidance that the Tissues and Cells Directive applies in these instances
which also govern the safety, efficacy and quality of cell products. Therefore,
a subtle shift in emphasis may be all that is needed, and guidance from
regulators would provide institutions with the confidence to continue
developing these novel therapies that possess the potential to influence the
future course of cell therapies.
Conclusion
Flexibility and clarity from the EMA defining an alternative
regulatory route could provide the security that academic or medical
institutions need to continue investing in and developing autologous cell
therapies. This clarity would provide for the fact that these autologous
treatments will not be compromised by the award of an MA for a similar process
elsewhere in the EU, while still maintaining product quality and patient
safety. Business models around centres of excellence producing unlicensed
autologous ATMPs could offer specialist autologous treatments without the costs
of seeking an MA. In this way, the potential of cell therapies to develop new
treatments will not be unnecessarily inhibited.
References
1. Regulation (EC) No 1394/2007 of the European Parliament
and of the Council on advanced