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European Biopharmaceutical Review

Cellular Therapy

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


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Dr Julian R De Havilland trained as a transplant immunologist in the UK, where he investigated innate immunity and experimental therapies for complement regulation in transplant recipients. In 2008, he joined the pancreatic islet transplant programme at the RoyalFreeHospitalin London, manufacturing allogeneic and autologous cell products. From May 2012, he has managed the GMP suite of cell therapy laboratories, which are part of the Newcastle Cellular Therapies Facility.

Anne Dickinson is Professor of Marrow Transplant Biology in Haematological Sciences, Institute of Cellular Medicine, Newcastle University, UK. She is also a Health Professions Council-registered Clinical Scientist and Director of the GMP, Human Tissue Authority and MHRA-licensed Newcastle Biomedicine Cellular Therapies Facility. Anne directs a clinical research laboratory employing PhD students, research associates and Marie Curie fellows. She currently coordinates a European Commission-funded FP7 Marie Curie Initial Training Network called ‘Celleurope’, developing novel cellular therapies for haematopoietic stem cell transplantation, as well as the assessment of cellular and genomic biomarkers. 

Anne Black is Assistant Director of Pharmacy-Quality Assurance at Newcastle upon Tyne Hospitals NHS Foundation Trust. She is a pharmacist and a Qualified Person for Investigational Medicinal Products. While most of her experience is in traditional pharmaceuticals, she has developed an interest in advanced therapy medicinal products and is involved with the quality management of the Newcastle Biomedicine Cellular Therapies Facility.

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Dr Julian R De Havilland
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Anne Dickinson
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Anne Black
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