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European Biopharmaceutical Review

Off the Beaten Track


Novel biopharmaceutical therapies in the past have faced a challenging regulatory journey due to their uneasy relationship with traditional health product categories. The European Commission’s establishment of the latest category, advanced therapy medicinal products (ATMPs), opens up new pathways for commercialising these products in the EC.


Historically, therapies frequently included the use of drugs containing active pharmaceutical ingredients (APIs), comprised of low molecular weight substances. These were commonly referred to as small molecule drugs and the accumulated understanding of synthesising and modifying such small molecules combined with current insight into biological processes continues to prove productive. One example of the successful combination of molecular insight into pathological mechanisms combined with small molecule expertise might be the drug Gleevec®, often successfully treating the previously lethal disease chronic myelogenous leukaemia (CML) (1).

Following the advent of monoclonal antibodies, it was recognised that these molecules offer significant therapeutic value by virtue of their ability to recognise highly specific structures, modulating, for example, inflammatory processes. The molecular weight of drugs derived from antibodies (for example, 160,000Da) compared to that of a typical small molecule drug (for example less than 800Da) might be indicative of the increased complexity of such drugs imposing new challenges regarding characterisation and quality control. More recently, entire cells, genetic modifications and indeed tissues have been developed as therapeutics and these, by the same standard, are more complex still. Consequently, the regulatory path towards approval for such therapeutics has taken time to evolve. This article discusses this path and its status.

Evolution of the Regulatory Pathway

Two classes of products in aid of human health have been established: firstly, medical devices such as pacemakers and dialysis devices, or auxiliary items such as tubing used for medical purposes; and secondly, medicinal products, such as substances of pharmaceutical activity – ‘drugs’. To obtain approval for the latter, two criterion need to be met – approval of the manufacturing facility/processes (a manufacturing license) and successful clinical trials. Clinical trials especially have evolved to help protect patients from harm – something in previous times not always a given – and help protect vulnerable classes of individuals in particular, as well as to warrant reliable data to be derived from work with human subjects (2).

Part of the evolution of the regulatory pathway for drugs such as cells, tissues and gene therapies was that, in the absence of specific legislation, such drugs were not fully covered by legislation and, as a consequence, legally on the market in EU Member States such as Germany once the competent authorities had issued a manufacturing license. As such, certain celland tissue-based drugs were legally on the market in Germany without having gone through clinical trial evaluation and the corresponding reviews (3).

EU member states recognised this gap and put forward specific legislation which culminated in the EU regulation 1394/2007 for advanced therapy medicinal products (ATMPs) (4). This regulation now provides an EU-wide standard for the approval process for therapies based on cell therapy, tissue engineering and gene therapy approaches, and made the EU Centralised Procedure (CP) mandatory for regulatory approval of Marketing Authorisation Applications (MAA). The regulation came into force as of December 2008 and contains a transition phase such that all covered drugs already legally on the market are required to comply with the regulation by the end of 2011 (end of 2012 for tissueengineered products).



Cell Therapy – An Example of Advanced Therapy Medicinal Products

The use of cells and preparations thereof has long been recognised as useful, with blood transfusions in the 1800s considered the earliest example. In the 1950s it was recognised that bone marrow transplantations had utility in regenerating the recipients blood system when the recipients' own blood system had been destroyed, for example in case of leukaemia.

In the 1970s the first reports surfaced describing fibroblastic cells from bone marrow – cells not considered part of the blood system – which appeared to have the ability to form connective tissues such as bone (5). Subsequent work has demonstrated the utility of such cells in regenerating not only connective tissues such as cartilage and bone, but also in aiding heart regeneration upon infarction and, perhaps surprisingly, also in modulating the activity of the immune system such that, for example, autoimmune diseases may be treated (6). Possibly connected to this latter utility, it has also been recognised that such fibroblastic stem cells from bone marrow, often referred to as mesenchymal stem cells (MSCs), do not appear to elicit immune responses from the recipient (7). While the underlying mechanisms are not fully understood, this has been the basis for considering such cells as therapies which may be applied not only in a recipient-specific context (autologous), but also in a non-recipient specific context (allogenic). This facilitates the manufacture of large lot sizes (as opposed to lot sizes for one individual only) and concomitant economy of testing for specifications – thus setting the stage for widely available therapies based on such stem cells; importantly, allogenic products are readily available when needed.

Approvals: Manufacturing License

One feature of ATMPs is that they are often applied systemically or localised surgically, and therefore it is paramount for microbial contaminations not to be introduced. This is of particular importance since, especially in the case of tissue engineered products, manufacturing processes may be lengthy, manual and complex, hence increasing risks of microbial contamination. Such products often contain living cells or other structures incompatible with terminal sterilisation prior to application. Consequently, the requirement for sterility throughout manufacturing must be taken into account when designing both the manufacturing plant and process. The former is covered by Annex 1 to EU GMP guidelines and the latter by general EU GMP guidelines, and it is the conformity with these which is in the focus of inspections preceding manufacturing licenses.

Perhaps of particular importance for ATMPs are reviews of raw materials, as these may be of non-pharmacopoeia quality. Often, cell-based products derived from R&D projects are chosen for functionality rather than quality and regulatory compliance. Perhaps the greatest challenges in this regard are products of animal origin (POAs). In principle, POAs carry the risk of introducing animal pathogens, as highlighted by the European Medicines Agency (EMA) 2004 topic on transmissible spongiform encephalitis (TSE).

Currently, most cell culture media used for adherent cell culture depend upon bovine serum, providing factors required for successful cell culture such as growth factors and adhesion molecules. The EMA requires reducing the level of infectious agents, currently accomplished by -irradiation. The European Directorate for the Quality of Medicines (EDQM) provides certificates for sera which satisfy their criteria, and it is useful to select suitable sera from amongst these. The same logic applies to auxiliary agents such as enzymes.

These topics are part of the reviews and inspections leading to manufacturing licenses issued by government agencies such as Germany’s district governments (Bezirksregierungen). In some countries these are not central agencies, therefore there may be local specifics, so it is particularly advisable to approach and involve these bodies early in the design phase to avoid issues later on.

First Contact with EMA: The Innovation Task Force

In addition to the various formalised paths to contact EMA, the Innovation Task Force (ITF) provides an interesting approach to a first and informal sharing of information with the agency. The ITF is a multi-disciplinary group which, within 60 days of receipt of a valid request, arranges free meetings where potential applicants may share information and receive early guidance.

Does a Product Constitute an ATMP?

A very early decision to be made is whether a product is indeed considered an ATMP. Regulatory bodies have published decision trees which may be used to determine whether a particular product is considered an ATMP or not. Important criteria for a product being considered an ATMP include: whether the product includes cells or tissues, whether these were substantially manipulated, whether regenerative potential is ascribed to the product, whether it includes live cells or tissues and whether its main functions are either pharmacological, metabolic or immunological. Additional criteria includes whether products contain recombinant nucleic acids or APIs manipulating the activity of a nucleic acid once applied to humans, and whether their activities are directly related to this nucleic acid or its expression products.

Official classification can be obtained from the Committee for Advanced Therapies (CAT). For this to occur, CAT offers advice and forms, and requires the assessment of the manufacturer itself on the nature of the product. Importantly, it is bound to provide answers within 60 days of submission; this does not, however, preclude additional questions for the manufacturer which may add to the time frame. The potential scope of scientific advice offered by EMA is by no means limited to the above and may extend to pre- and clinical stage development issues such as potential orphan drug status.

ATMP Certification Procedure

EMEA offers a service to small and medium sized enterprises (SMEs) referred to as ‘certification’. This is intended to provide manufacturers with an official review of quality data as well as preclinical data if available. While all data will have to be included in later submissions and the certification procedure is not legally binding, it is likely to foster dialogue with the agency and to obtain a plausible ‘stamp of approval’ for work done thus far – quite possibly a valuable tool for companies in demonstrating to third parties such as investors that progress has been made and has been reviewed by an independent agency. EMA provides an initial time line of 90 days for issuing such certifications – this period may increase if site visits and further questions are deemed necessary.

Clinical Trials and Beyond

At this point, the treatment of ATMPs converges with other medicinal product candidates and follows established procedures for clinical trials: authorisation by national competent authorities, good clinical practice and market authorisations issued by the European Commission after a successful completion of the centralised procedure.

With the now-established ATMP regulation and the various tools provided by the competent authorities, developing ATMP products has become a guided process with EU-wide standards. While developing ATMPs remains a complex and challenging endeavour, the regulatory path has been straightened so that we can now focus on challenges inherent in these technologies.

Acknowledgement: The author would like to thank Günter Hennings, PhD, of HGH Regulatory Sciences for critically reviewing the manuscript.

References

  1. Druker BJ, ST1571 (Gleevak) as a paradigm for cancer therapy, Trends in Molecular Medicine 8(4): ppS14-S18, 2002
  2. Visit http://www.fda.gov/AboutFDA/WhatWeDo/History/ ProductRegulation/SulfanilamideDisaster/default.htm
  3. Visit http://blogs.nature.com/news/2011/05/notorious_stem_cell _therapy_ce_1.html
  4. Visit http://ec.europa.eu/health/files/eudralex/vol-1/ reg_2007_1394/reg_2007_1394_en.pdf
  5. Friedenstein A and Kuralesova A, Osteogenic precursor cells of bone marrow in radiation chimeras, Transplantation 12(2): pp99-108, 1971
  6. Barry F and Murphy, JM, Mesenchymal stem cells: clinical applications and biological characterization, The International Journal of Biochemistry & Cell Biology 36 (2004) pp568-584
  7. Aggarwal S and Pittenger MF, Human mesenchymal stem cells modulate allogenic immune cell responses, Blood 105(4): pp1,815-1,822, 2005


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Christian van den Bos is Executive Programme Manager at Lonza, where he drives development efforts for advanced therapeutic stem cell products. Christian has 16 years of experience in cell therapy and has managed cell therapy projects ranging from early R&D to production, regulatory and clinical trials. Prior to joining Lonza, Christian held senior positions in Cytograft, Symetis, Viacell Europe and Spectra Stable Isotopes, and served as Senior Scientist for Osiris Therapeutics. He has a PhD from the University of Münster and an MSc from Oxford University. Christian has served as reviewer for several scientific publications, has published on regulatory approaches to cell therapy products and is recognised as a qualified person (QP) according to EU drug law. Email:  christian.vandenbos@lonza.com
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