Standing Together (in: European Biopharmaceutical Review, January 2017, p. 60-63)

– Christian van den Bos, Somaiah MN, Beate Walter

As the need to cure genetic diseases grows, so too does the requirement for pharma companies to strictly adhere to the relevant legislative guidelines. But with so many sets of criteria, exemptions and exceptions to the rules, innovators are finding the process difficult


Two types of medical products were previously known in the EU regulatory framework. Firstly, medicinal products (for example, drugs) and secondly, medical devices comprising simple objects such as tubing, as well as complex instruments like pacemakers. Scientific discoveries have led to the development of additional entities such as active pharmaceutical ingredients. On the one hand are proteins like antibodies, and on the other hand are living cells and tissues.


Beyond cells and cell aggregates considered for replacing diseased tissue, genetic engineering has provided the tools to address genetic diseases, so that constructs containing recombinant nucleic acids have also become drug candidates. Products generated by these technologies fitted into neither of the existing classes of medical products so that, at the time, a manufacturing license was often sufficient to put such new medical products onto the market. Recognising these new scientific developments, as well as the gap in the existing regulatory framework, a new class of medicinal products was created in the EU and was termed advanced therapy medicinal products (ATMPs).


ATMP Regulation

This new class of medicinal products comprises all of the above; that is, products derived from principles of cell therapy, tissue engineering and gene therapy.


At the core of the newly created regulatory framework is the EU regulation 1394/2007 – here referred to as ATMP regulation – that came into force in 2008. Being a regulation rather than a directive, it immediately became effective across the EU.


The ATMP regulation provided a unified environment for the EU, as well as clarity unto the clinical development path of ATMPs. The advent of this unified setting for new and innovative products was generally lauded and perceived as a tool to accelerate development of access and marketing of such products. Perhaps due to the recognition of the sometimes complex nature of these products – and the often small- or medium-sized nature of enterprises (SMEs) involved in producing them – incentives have been offered to innovators. These include scientific advice, the opportunity of having preclinical data certified, as well as a possible fee reduction for SMEs.


Beyond the central path to a marketing authorisation and perhaps acknowledging the need for advancing individualised therapies, the ATMP regulation provided an exception. Specifically, ATMP products that do not meet the criteria are to be made exempt from the

ATMP regulation, and to be approved by national authorities. These excluded products need to be:

  • Produced on a non-routine basis
  • Created according to specific quality standards
  • Used in the same member states (as manufactured)
  • Utilised in a hospital
  • Used under the exclusive professional responsibility of a medical practitioner
  • Given as a personalised medical prescription for custom-made products for the individual patient


As of 2016, the ATMP regulation has been in force for eight years. The current total of products approved according to this regulation has recently been published by the relevant government bodies.


The Paul Ehrlich Institute (PEI), the relevant German authority, cites a total of five such approved products in July 2016 (1). Considering the substantial time passed since the ATMP regulation came into force, the size of the potential market, the number of development projects in this area and the amount of public funding having gone into the development of such products, one is inclined to conclude that this number is far below expectations.


Factors contributing to this situation might include the sometimes experimental nature of such products leading to development setbacks; unusual and often complex animal- derived ingredients raising quality and regulatory concerns; and the SME disposition of many businesses operating in this space sometimes associated with a limited ability to support extensive development processes. These companies can struggle to meet the challenges involved in bringing such complex products to market, although they may also consider their advantages. Some – certain chimeric antigen receptor T cell technologies, for example – can offer lifesaving benefits for patients previously thought terminally ill. Assuming clinical studies support the initial impression, one might expect a few questions as to their gain. Other products, including some perhaps not stringently tested prior to the ATMP regulation, may exhibit a less defined benefit and could, therefore, find it difficult to withstand the rigour of controlled clinical studies.


Given the limited number of products approved through the central ATMP route, it is no surprise that alternative regulatory options are viewed with interest. As aforementioned, the ATMP regulation – specifically Article 28 – stipulates that ATMPs adhering to the criteria listed above can be exempted from the centralised pathway, and are to be regulated by national legislation. Germany, for instance, has implemented this requirement in Paragraph 4b of its medicinal product act (Arzneimittelgesetz), corresponding with the text found in the ATMP regulation.


For ATMPs fitting the brief, it appears to be possible to treat patients without clinical trials, while charging for treatment. This would drastically simplify the development path for innovators and, consequently, one might expect a rush into this particular regulatory choice.


The Hospital Exemption

However, apart from the criteria mentioned above, the application (Module 5, section 2) requires an explanation as to why the patient cannot be treated adequately with currently licensed products or other available treatment options (2). In addition, it has been suggested that this might help to counter the argument that the hospital exemption (HE) provides for undue competition to products authorised by the central procedure, but whether this holds true remains to be seen (3).


Currently, the number of products approved through this pathway by PEI stands as seven (1), which compares to the five listed as authorised through the central process. However, this number refers to only those licensed through the HE in Germany. For a correct comparison, products approved in all EU member states by the HE should be tallied and, even though hard numbers are not obvious to identify, it is likely that the total of products authorised nationally through the HE exceeds that of the ones approved centrally by far.


The seven products currently authorised through the HE mechanism in Germany include those in which the patient’s cells are treated extra-corporally – such as a dendritic cell cancer vaccine, or cytokine activated killer cells – as well as autologous cell preparations. These involve bone marrow- derived progenitor cells (t2c001), cartilage/chondrocyte preparations, preparations of mucosal cells (Mukocell), alongside cartilage products like Bioseed, ChondroCelect, Chondrosphere and Novocart 3D.


The nature of these products is what one might expect, given the conditions for inclusion listed above. However, there are additional criteria that might be worthwhile to examine. Within the decision tree presented by PEI, one section could deserve particular attention – namely the one entitled ‘The ATMP is not manufactured routinely’, as it appears to offer three ways to comply with the requirement (4). Firstly, and perhaps the most straightforward, the ATMP needs

to be produced in small quantities, and medically justified modifications to be made in the manufacturing process with a view to an individual patient. Secondly, if this is not the case, ATMPs that “have not been manufactured in quantities sufficient for comprehensive assessment” are deemed eligible. Thirdly, if the first two do not apply, ATMPs “not manufactured routinely for other reasons” are considered eligible, too.


These statements might be interpreted such that legible ATMPs fall into two groups: strictly patient-specific products, or products which, in principle, can be industrially manufactured – but simply have not been manufactured in quantities sufficient to warrant a comprehensive assessment (for example, in clinical studies). Therefore, in Germany, this regulatory pathway might be open to products that are characterised by their novelty or early development status rather than exclusively by their patient-specific nature.


Importantly, it might offer access to treatments not

yet marketed to patients. Patients without established treatment options – due to orphan diseases, comorbidities, concomitant diseases or other genetic preconditions, for example – might be desperate for novel treatment options and, consequently, equally desperate to gain access to products not yet authorised. Companies conducting clinical trials, however, are reluctant to include subjects not meeting the rigorously selected inclusion criteria, in order not to jeopardise the success of this particular drug development. Segregating the clinical development path into one following clinical studies and the other following the HE might help ease this issue (3).


Asia-Pacific Situation

India, one of the leading drug manufacturing countries, often generics, faces new biologicals similar to the EU classification of ATMPs (5); and Japan, motivated by the discovery of induced pluripotent stem cells by Shinya Yamanaka (6), and the subsequent awarding of the Nobel prize (7), has laid out an accelerated path to market for such products (8). Consequently, it seems pertinent to undertake a cursory review of potential similarities and differences between the EU and the Indian, as well as Japanese, regulatory specifics.



The National Apex Committee for Stem Cell Research and Therapy was formed by the Indian Council for Medical Research (ICMR) and the Department of Biotechnology (DBT) in 2010 to oversee and monitor the activities in the field of stem cell research, which became operational in October 2012. Within the Biological Division in Central Drugs Standard Control Organisation (CDSCO), a Stem Cell Division has been established for the internal evaluation of all proposals, including stem cells concerned with clinical trials and marketing authorisations.


Similarly, the Ministry of Health and Family Welfare constituted a core investigational new drug panel of experts named Cellular Biology Based Therapeutic Drug Evaluation Committee under the chairmanship of the Director General of ICMR and the Secretary of the Department of Health Research. The aim was to advise the Drugs Controller General of India in matters pertaining to regulatory pathways leading to the approval of clinical trials and market authorisation for ‘therapeutic products derived from stem cells, human gene manipulation and xenotransplantation technology’ in September 2010.


ICMR and DBT rolled out National Guidelines for Stem Cell Research in December 2013 to ensure that research with human stem cells is conducted in a responsible and ethical manner. This guideline emphasises the fact that stem cells are not part of standard of care and are investigational at present. In the same way, CDSCO established a committee in June 2013 to suggest a roadmap for regulation of stem cells and other cell- based therapies practised in India. Accordingly, a draft guidance document for regulatory approvals of stem cell and cell-based products (SCCPs) was introduced in December 2013 to control the usage of SCCPs for regenerative medicine in India.


There are about 67 clinical studies with stem cells that were either initiated, ongoing, on hold, or completed as per the clinical trial registry of India. No stem cell product has obtained marketing authorisation in India at the time of writing this article (9).


The intention of adopting a regulatory framework to commercialise stem cell products began in India in 2010 – however, the status quo remains despite having formed an impressive number of committees to safeguard patients. On the other hand, several new drugs have been granted marketing authorisation in India without conducting Phase 3 studies with Indian subjects. To name a few: Pertuzumab (Roche), Rixubis (Baxter), Pasireotide (Novartis), Ibrutinib (Johnson & Johnson) and Obinutuzumab (Roche). These may serve as a model for getting advanced therapies into the market.



The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan implemented a new regulatory framework in November 2014 for regenerative medicine products (RMP) considering the importance of earlier access of these products by the patients for unmet medical needs. The PMDA has revised the Pharmaceutical Affairs Law for RMP and Japan’s parliament has enacted the bill. This bill allows the Japanese government to grant conditional approval to such products if their safety is confirmed, and expectable efficacy trends are demonstrated in early stage of clinical trials, as may occur on completion of Phase 2.


Given these examples, one might suggest that India should frame or consider adopting a robust regulatory pathway that can provide early access to regenerative medicine to patients, similar to the PMDA model or the German HE.


The central ATMP market authorisation procedure has, thus far, yielded only a modest number of approved products. Consequently, alternative regulatory options are gaining increased attention by both patients and innovators.


Specifically, the HE has been, and is likely to continue to be, a critical element in making highly innovative ATMP products available – patient-specific or otherwise. We believe that it should not be viewed as a solitary alternative to the centralised procedure, but as a bridging tool serving innovators and patients alike – by providing access to advanced therapies not yet authorised, particularly to patients with limited choices.



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  3. Schnittger A, The Hospital Exemption – A regulatory option for unauthorised advanced therapy medicinal products, MSc thesis, University of Bonn, 2014
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About the authors

Dr Christian van den Bos founded Mares Ltd in 2007 to accelerate the development of regenerative medicinal products, and currently serves as its Managing Director. Based on his experience, Christian has been recognised as a Qualified Person according to EU drug laws for cell-based medicinal products. He underwent postdoctoral training at Cold Spring Harbor Laboratories, US, and earned a PhD at the University of Münster, Germany and an MSc at the University of Oxford, UK.


Somaiah MN is a senior regulatory affairs professional with multifunctional regulatory, clinical and quality assurance experience, from the pharma, biotech and stem cell industries. His background includes working for AstraZeneca, Bristol-Myers Squibb, Mallinckrodt and Biocon, as well as technical expertise in drug product registration, clinical trial registration and an intimate knowledge of regulatory framework in pharmaceuticals.


Beate Walter, PhD, is a Medical Writer at CONVIDIA Clinical Research GmbH, and is well experienced in publication management and medical writing. Before CONVIDIA, she worked as a postdoctorate in preclinical research covering infectiology, oncology and biochemistry. Beate has a PhD and an MSc from the University of Münster, Germany.


This article is taken from:
European Biopharmaceutical Review, January 2017, p. 60-63 (Download)

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