Advanced therapy medicinal products

The increase of scientific knowledge and technological innovation in the fields of biotechnology, cell biology and medicine has led to the development of new therapies. Advanced therapy medicinal products (ATMPs) are a novel class of medicines that offer potential treatment opportunities for diseases that currently have limited or no therapeutic options,(1–4) such as metabolic disorders, haemophilia, cystic fibrosis and muscular dystrophies among others.(4)

In contrast to most medicines, ATMPs have to be authorised through the centralised European Medicines Agency (EMA), which governs all Europe.5 Although, in the past, there was a lack of an European-wide regulatory framework, the regulation on advanced therapies (Regulation EC 1394/2007) has been designed to ensure the free movement of advanced therapy products within Europe, to facilitate access to the EU market and to foster the competitiveness of European companies in the field, while guaranteeing the highest level of health protection for patients (www.ema.org).

This article summarises what ATMPs are, how their regulation is performed and what their challenges are. Some examples of ATMPs registered in Europe are provided.

The term ‘advanced therapy medicinal product’ can be defined as a biological medicinal product that can be classified as either gene therapy medicinal products (GTMPs), somatic cell therapy medicinal products (CTMPs), tissue-engineered medicinal products (TEMPs) or any combination of the three.(1,2,6)

GTMPs are biological medicinal products with the following characteristics:

CTMPs are biological medicinal products with the following characteristics:

TEMPs are products that contain/consist of engineered cells or tissues and are presented as having properties for or are used in/administered to humans with a view to regenerate, repair or replace a human tissue.

Combined ATMPs incorporate a medical device and include viable cells or tissue parts or, in cases of non-viable cellular/tissue parts, the primary mode of action is attributed to the cell component as either pharmacological, immunological, metabolic or as having repair, replacement or regeneration qualities.

Regulatory aspects for marketing authorisation in Europe

ATMPs were classified by two European Directives (2003/63/EC and 2009/120/EC) and regulation (EC) number 1394/2007 of the European Parliament and of the Council.(2,6–8) These regulatory changes cause a change of requirement for manufacturing of ATMPs, similar to their application to humans. The regulation 1394/2007 aims to facilitate the patient access to these products and to foster the competitiveness of European pharmaceutical companies in the field, guaranteeing the highest level of protection of patients’ health.(2,7)

Because of the complexity of ATMPs, a new Committee for Advanced Therapies (CAT) has been installed at the EMA. It provides a multidisciplinary team of experts representing all member states of the European Union, and countries from the European Economic Area and the European Free Trade Association, to assess the quality, safety and efficacy of ATMPs, and to follow scientific developments in the field of ATMPs.(2,3) The main responsibilities of the CAT are:

Examples of ATMPs products that have been granted centralised marketing authorisation (recognised by their marketing authorisation number

starting with characters EU/… ) or a national authorisation (recognised by their authorisation number starting with characters PEI/…) include:

Glybera^® (UniQuere Biopharma, The Netherlands) was granted European Commission marketing authorisation in October 2012 (EU/1/12/791/001) under exceptional circumstances as a treatment for adults diagnosed with familial lipoprotein lipase deficiency confirmed by genetic testing, and suffering from severe or multiple pancreatitis attacks despite dietary fat restrictions.(2,8)

Lipoprotein lipase deficiency is a very rare disease in which patients lack the gene to produce lipoprotein lipase, an enzyme responsible for breaking down fats in lipoproteins (fat-carrying particles in the blood). The active substance, alipogene tiparvovec, uses a modified virus carrying a gene for lipoprotein lipase. The virus used in Glybera^® is an ‘adeno-associated viral vector’ that has been modified so that it cannot make copies of itself. The virus does not cause infections in humans.

Provenge^® (Dendreon, UK) was granted marketing authorisation in 2013 (EU/1/13/867/001). It consists of autologous peripheral blood mononuclear cells activated with PAP-GM-CSF (Sipuleucel-T). It is indicated for treatment of asymptomatic or minimally symptomatic metastatic (non-visceral) castrate resistant prostate cancer in male adults in whom chemotherapy is not yet clinically indicated.(2,9)

ChondroCelect^® (TiGenix, Belgium), an autologous product containing chondrocytes for treatment of deep cartilage injuries of the knee, has received positive opinion for marketing authorisation (2009, EU/1/09/563/001). During osteoarthritis degenerative processes, major modifications of articular cartilage are observed at the tissue, cellular and molecular levels. Articular cartilage, if damaged, may lead to the subsequent development of osteoarthritis lesions, which is of major public health concern. Pharmacological treatments and tissue engineering are combined towards regenerative medicine to induce cartilage repair.(10)

MukoCell^® (UroTiss, Germany) has been granted authorisation (PEI.A.11491.01.1, December 2013) for distribution in Germany. It provides a new treatment option for urethral repair that uses the patient’s own cells as a transplant. The replacement tissue is cultured from the patient’s own cells, incorporated into the surrounding tissue within a short amount of time and develops into new, fully functional urethral tissue. To make the graft, a biopsy is performed to extract a small amount of tissue from the patient’s mouth. Within a period of three weeks, this is used in a cleanroom laboratory to cultivate the tissue replacement of the required size. Finally, the patient’s tissue replacement is shipped under sterile conditions to the clinic for transplantation.(11)

MACI^® (Genzyme, The Netherlands) was granted EU marketing authorisation in June 2013 (EU/1/13/847). It is an implant used to repair cartilage defects at the ends of the bones of the knee joint. It consists of the patient’s own cartilage cells on collagen membranes, which are implanted into the cartilage defect in the knee. The cells are used to fill in the space where the cartilage has been damaged, thereby regenerating the damaged areas and helping to resolve the patient’s symptoms, such as pain and problems moving the knee. MACI is used to repair full-thickness defects with a surface area of between

3 and 20 cm2 in adults who are experiencing symptoms (such as pain and problems moving the knee).(12,13)

During the first stage of treatment, a sample of cartilage cells is taken from the patient’s joint and grown in a laboratory. Then, the cells are placed onto the collagen membrane. Around six weeks later, the surgeon shapes the membrane to fit the damaged area in the knee cartilage and then implants it using a surgical procedure. A type of glue made from blood clotting proteins is used to hold the implant in place on the cartilage.(12,13)

Apart from registered ATMPs, ATMPs in clinical trials and unregistered products in a hospital are described as ‘hospital exemption’. The hospital exemption is applicable to all ATMPs that are prepared on an non-routine basis, prepared according to specific quality standards, used within the same member state, used in a hospital, used under the exclusive responsibility of a medical practitioner and which comply with an individual medical prescription for a custom-made product for an individual patient.(3,14) Considering the definitions, hospital pharmacists are involved in the preparation of ATMPs. If ATMPs are a hospital exemption, the hospital pharmacist will need an organisation and a facility to manipulate and deliver these products, especially as he or she is responsible for the quality (in accordance with good manufacturing practice (GMP) guidelines for human medicinal products for human use) and pharmacovigilance.(15)

Although member states are responsible for the implementation of the hospital exemption, there is a lack of clear guidance in most member states so far.

As ATMPs enhance the role of hospital pharmacists, increased training becomes mandatory to develop insight into these new technologies, which involves a stepwise process to become familiar with high technological and scientific concepts. Competencies for pharmacists include theoretical and practical skills in molecular biology and cell biology, as well as their application to gene therapy, cell therapy and tissue engineering.(16) In addition, training in GMP for ATMPs and translational research related to hospital pharmacy opportunities are required (ATMP vehicle delivery, ATMPs pharmaceutical compounding, quality control, regulatory framework, etc.)(16) It poses logistical challenges (traceability) and product, quality and clinical concerns (safety and long-term efficacy; pharmaco-vigilance). Some universities already provide masterclasses for ATMPs (for example, University of Granada, Spain (www.atmp-masterinmanufacturing.com/) and University College London Cancer Institute, UK (www.ucl.ac.uk/cancer/educationevents/ccte).

As the innovative field of ATMPs is in rapid progression, numerous challenges arise from the derivation and nature of ATMPs. Pharmacists face these challenges so knowledge and training of hospital pharmacists will become mandatory.