Introduction

Advanced therapy medicinal products (ATMPs) are a category of innovative products comprising gene-therapy medicinal products (GTMPs),(1) somatic cell-therapy medicinal products (sCTMP)(2) and tissue-engineered products (TEPs).(3) The main therapeutic areas are oncology and regenerative medicine, particularly in the field of cardiovascular conditions and haematology.(4) Yet despite the harmonising EU legislation which has been in place since 2008, few products have reached the market in commercial form.

In 2014(5) the European Commission issued a report on the implementation of ATMP legislation to date.(6) On June 30 2014 the European Medicines Agency Committee for Advanced Therapies announced a public consultation on its revised guidance for ATMP classification.(7) The consultation ended on October 31 2014.

Regulatory and industry landscape

Regulatory landscape

ATMPs are biological medicinal products and, as such, are governed by pharmaceutical legislation, including the EU ATMP Regulation.(8)

The regulation builds on directives concerning medicinal products for human use,(9) quality and safety standards for human tissues and cells, medical devices(10) and active implantable medical devices,(11) as well as on regulations concerning centralised marketing authorisation procedures.(12)(13)

However, where ATMPs are derived or produced from human tissue and cells, not all phases of the manufacturing process fall within the regulation's scope. Notably, the donation, procurement and testing of the human tissue or cells involved in the manufacture of an ATMP are governed by EU Directive 2004/23/EC, which lays down standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells.(14) The directive is implemented at national level and sets out requirements for the accreditation, designation, authorisation or licensing for the procurement and testing of the biological material intended for human applications.

The need to comply with both the centralised procedure for marketing authorisations under the ATMP Regulation(15) and differing national directive requirements can create a substantial administrative burden or constraints in some member states.

By July 2014, 12 market authorisation applications had been submitted to the Committee for Advanced Therapies, while only four ATMP products had been granted market authorisation.(16) These low numbers can be explained partly by the fact that a significant number of ATMP developers active on the market before the regulation entered into force never applied for market authorisation.(17) A large proportion of those developers worked under the hospital or specials exemption. Consequently, the number of market authorisations granted since the entry into force of the regulation does not reflect the ATMP market accurately. The vast majority of ATMPs on the market are not covered by market authorisation.(18)

Industry landscape

Most research and development into ATMPs is conducted by academics, academic spin-offs, not-for-profit organisations and small and medium-sized enterprises (SMEs). Until now, only a few larger pharmaceutical companies have engaged in the investigative phases of ATMP development, due to the perception that the early investigative stages are high risk.(19)

An ATMP provides a number of incentives intended to stimulate research and development in this area. For example, the regulation grants SMEs a 90% fee reduction for scientific advice, which can be deferred until market authorisation is granted. SMEs are further entitled to a 50% reduction on market authorisation fees for products of particular public health interest to the European Union. SMEs do not have to pay any fees if market authorisation is not granted. The ATMP also offers non-SME applicants a 65% reduction of the European Medicines Agency's fees for ATMP-related scientific advice.

As the commission's report on the application of the regulation points out,(20) incentives are no longer offered for post-marketing obligations. Notably, the 50% fee reduction for market authorisation and post-marketing activities previously offered to SMEs and hospitals for ATMPs with a public health interest has been withdrawn. The report suggests that reintroducing such incentives could increase the number of products reaching the market, since post-marketing obligations can impose significant costs that may even be prohibitive for smaller companies before the ATMP becomes profitable.

Challenges and opportunities

The commercial development of ATMPs poses a number of challenges for developers – most notably, the following:

  • complex product classification;
  • burdensome procedures for ATMP-medical device combinations;
  • uncertainties surrounding certification procedures;
  • lack of harmonisation of import and export rules; and
  • divergent rules and procedures for critical aspects of ATMP development across different member states.

Product classification

The commission's report(21) identifies the classification of products as one of the practical difficulties in the application of the regulation. Among the issues encountered in practice are:

  • whether manipulation of a living material is to be considered substantial; and
  • the categorisation of certain innovative products that could qualify not only as medicines, but also as medical devices, cosmetics or tissues and cells.

The Committee for Advanced Therapies classifies ATMPs into three categories (GTMPs, sCTMPs or TEPs) according to their characteristics, mode of action and intended function.(22) For example, while sCTMPs are intended for the prevention, diagnosis and/or treatment of diseases via pharmacological or metabolic actions, TEPs are used for regenerating, repairing or replacing human tissue.(23)

While the committee classification recommendations are not legally binding, they constitute a valuable tool for ATMP developers – particularly since the classification helps the developer and the (national) competent authorities to identify the regulatory requirements, criteria and procedures to be applied in the later stages of product development.(24) Thus, the early classification of an ATMP is not only a matter of regulatory compliance, but it may also influence a developer's strategy and business model.

According to the committee, more clarity is required in this area, both in order to achieve the highest possible level of public health protection and to give developers and investors greater certainty regarding the applicable regulatory framework from the earliest stage of development.(25)

Combined ATMPs

Where an ATMP incorporates as an integral part of the product one or more medical devices, the combination may qualify as a "combined advanced therapy medicinal product".(26) While specific guidelines have been drafted with respect to these combined products,(27) the regulation nonetheless requires the medical device and medicinal product to be assessed separately. The European Commission's recent public consultation(28) revealed that stakeholders consider this excessively burdensome, especially in cases where the device is not marketed separately.

Stakeholders further reported that the separate assessment requirement incentivises the use of already approved devices rather than the development of new, better-targeted devices, based on the (not entirely correct) perception that recourse to an already CE-marked device will speed up the regulatory procedure. Thus, stakeholders argue that the existing system could negatively affect the overall quality and innovative nature of the products on the market.

For these reasons, stakeholders favour a single assessment procedure, in which the committee would evaluate both elements of a combined ATMP.(29)

Certification

SMEs developing ATMPs may apply to the committee for certification of quality and non-clinical data. Certification was designed to help SMEs attract investment for ATMP development. However, it has been used only five times since the regulation entered into force.(30)

There are several possible reasons for this. First, the link between certification and the market authorisation procedure is unclear. Second, the scheme has been limited by date, both in terms of who is eligible to apply and what is covered by the certification.

Thus, stakeholders in the commission's consultation suggest that the role of the certification should be clarified and its application extended to cover clinical aspects of the market authorisation application dossier, among other things. Finally, stakeholders argue that the scheme should also be opened to commercial entities.(31)

Import and export of human tissue and cells

Import and export of human tissue and cells, and intra-European distribution of such biological material, is a crucial aspect of ATMP manufacture. However, experience shows that differing quality and safety standards between member states can pose a challenge for ATMP manufacturing schemes. While the directive harmonises quality and safety standards for human tissue and cells intended for human applications,(32) some crucial elements still need to be put in place in order to achieve full harmonisation.

Two draft commission directives(33) intended to address this issue are being prepared and will cover:

  • the procedures for verifying the equivalent standards of quality and safety of imported tissue and cells; and
  • the coding of human samples.

These new rules are intended to further standardise and clarify the requirements applicable to samples imported into and distributed within the European Union. It is hoped that both directives will be published by the end of 2014 and, following a transition period of one year for transposition into national law, may enter into force by the end of 2016.

Disparities in regulatory framework between member states

Notwithstanding the increasing level of harmonisation of pharmaceutical law in general, and ATMP legislation in particular, disparities remain between national rules in member states. This is in large part due to the fact that the regulation builds on legislation relating to quality and safety standards applicable to human tissue and cells, including EU Directive 2004/23/EC. Since this underlying legislation consists of directives, which leave member states to decide how to implement their requirements, ATMP developers are often confronted with a patchwork of divergent approaches that further complicate the process of obtaining market authorisation for an ATMP.

National implementation of tissues and cells legislation

One area in which member states have adopted divergent approaches under the directive is the regulation of tissue establishments. Experience shows that this can lead to practical and administrative difficulties, especially in the framework of cross-border activities.

In particular, ATMP manufacturers operating in different member states will need to comply with different administrative requirements depending on the member state in question. For example, some member states require periodic submissions to an ethics board, higher levels of personnel qualifications or manufacturing activities to cooperate with healthcare institutions under the supervision of local authorities.

Development activities under national supervision

Different requirements also apply for many development activities, which remain largely with national authorities. In particular, national authorities are responsible for the authorisation of clinical trials and granting manufacturing authorisation for investigational ATMPs.(34)

Exemptions from market authorisation obligation

Exemptions from the obligation to obtain market authorisation are regulated at national level. For example, member states may exempt certain products used on a non-routine basis for unmet clinical needs – EU Directive 2001/83/EC provides an ATMP-specific exemption, known as the hospital exemption(35) and ATMPs may also qualify for a specials exemption.(36) Other derogations may also be available under national law.

The differences in the way that these exemptions are applied between member states risk fragmenting the EU market and make it difficult for companies to foresee and manage associated costs and resources.(37) They may also result in the exemptions being applied more widely in some member states than others, with the risk that the number of applications for marketing authorisations is reduced.

The fact that the hospital exemption (unlike the specials exemption) is still available after a competing product has been approved can constitute an additional discouraging factor for ATMP developers.

According to the commission's March 2014 report,(38) it is anticipated that proposals will be made in order to further harmonise the conditions under which exemptions are possible as well as the requirements attached to that exemption. The objective is to strike a better balance between the need to ensure that ATMPs are made available to patients only after their quality, safety and efficacy have been demonstrated, and the need to facilitate early access for new treatments in case of unmet medical needs.

Comment

With the adoption of the regulation, the European Union is attempting to implement an open market for ATMPs, in which quality standards are consistently applied and adequately monitored.

The commission's report on its public consultation (published March 28 2014) identifies a number of issues encountered during the first years of the regulation's implementation. It also highlights areas in which the legislation could be improved – for example:

  • clarifying the scope of the regulation by fine tuning ATMP definitions;
  • adopting a more harmonised approach to market-authorisation exemptions; or
  • improving the under-used certification scheme.

It is yet to be seen which of the commission's proposals will be implemented as amendments to the regulation. The difficulties encountered in the early years of the regulation's application demonstrate that it is difficult to strike the appropriate balance between ensuring a high level of public health protection, creating conditions that facilitate the development and marketing of new treatments, and constantly adapting to rapid scientific progress.

Achieving these goals so that ATMPs deliver their full potential will require further harmonisation of the regulatory framework. This in turn will demand open and constructive debate among all stakeholders at every stage of the ATMP lifecycle, from early research to market approval and beyond.

Marc Martens & Nicolas Carbonnelle

This article was first published by the International Law Office, a premium online legal update service for major companies and law firms worldwide. Register for a free subscription.