Regulation and manufacturing
The development and manufacturing of RM products is governed by several regulatory frameworks. Within the EU, regenerative medicine products that entail the transfer and expression of genes, or the use of cells that have been substantially manipulated or which are used in a ‘non-homologous fashion’, and that are industrially manufactured in order to be placed on the EU market will fall-under the jurisdiction of the medicinal products regulatory framework (Directive 2001/83/EC), and more specifically the Advanced Therapy Medicinal Products (ATMP) regulatory framework. The framework stipulates that ATMPs must be approved at the European Level by the European Medicines Agency, including the Committee for Advanced Therapies (based on evidence of quality, safety and efficacy) before they can be placed on the market, and that all ATMPs must be manufactured in a GMP licensed facility. It is the responsibility of the Member State’s national regulatory body – the Medicines and Healthcare products Regulatory Agency (MHRA) in the UK - to ensure that facilities are licensed appropriately (Directive 2003/94/EC). Indeed, a manufacturing authorisation is required both for medicinal products (article 40, Directive 2001/83/EC) and investigational medicinal products (article 13, Directive 2001/20/EC). In that context, the European Commission is preparing guidelines on GMP specific to ATMPs. After a first public consultation in November 2015 that gave rise to 48 contributions, the guidelines have been deeply improved and opened to a new public consultation that ended in September 2016. It aims to capture the complexity and risks associated with ATMPs manufacturing while recognising some flexibility necessary to the specific characteristics of their manufacturing. Products that are not classed as ATMPs, but which entail the use of human tissues and cells, will be governed by the Tissue and Cells Directives (2004/23/EC, 2006/17/EC and 2006/86/EC) which outline mandatory standards for sourcing materials. All facilities in which activities of testing, processing, preservation, storage or distribution of human tissues and cells intended for human applications are undertaken have to be accredited, designated, authorised or licensed by the national competent authorities (Article 6, Directive 2004/23/EC). In the UK, the Human Tissues Authority (HTA) and the Human Fertilisation and Embryology Authority (HFEA) are responsible for implementing these standards and for granting the tissues and cells establishments’ licenses. Regulatory provisions do permit the use of unlicensed ATMPs outside of clinical trials. The Hospital Exemptions provision enables nonroutine use of custom-made ATMPs within a hospital, prescribed by a medical practitioner for an individual patient. The way in which this provision is actually applied by Member States has differed, and the MHRA has taken a cautious, conservative stance. In the UK there is also a ‘Specials’ scheme which permits clinicians to prescribe unlicensed products (which can extend to ATMPs) to meet the special (clinical) needs of individual patients. The MHRA is responsible for granting ‘specials’ and ‘hospital exemption’ licenses to manufacturing facilities, and in both provisions, the products must be produced under GMP conditions. The ‘specials’ scheme, unlike the hospital exemption one, permits products to be imported or exported. Navigating the regulatory systems can be complicated, and the ATMP framework is generally seen as a regulatory hurdle for manufacturers and clinicians. Considerable costs are involved in adhering to the framework, potentially placing academic institutions and SMEs at disadvantage. Some special provisions have been established at EMA for SMEs (certification procedure, fees reductions, SME Office) but are not available to academic centres (this exclusion has been a point of contention). These considerations are probably one reason why currently many products under development seek ‘orphan’ status, which reduces the regulation fees required, and provides other regulatory incentives (protocol assistance, 10 years of market exclusivity). Although targeting only small numbers of patients with ‘rare diseases’, the particular and often unmet medical needs of those patients may also increase the willingness of commissioners to reimburse providers. Given the high degree of technical uncertainty in the field, regulators encourage that manufacturers engage with them earlier in the development process. This is particularly true both at the European level at EMA, and in the UK where Innovation, Regenerative Medicine and/or SMEs Offices have been established.
