The fast development of healthcare biotechnology represents a challenge to the legislator, both at a European and national level. The European Advanced Therapies Medicinal Products Regulation, now also known as Regulation 1394/2007 (the “ATMP Regulation”)2, will enter into force by the end of this year. It will be directly applicable throughout the EU.3
However, some issues are left open by the ATMP Regulation, as the European authorities have chosen to create an "ethically neutral" framework. This article intends to provide a brief summary of the history of the ATMP Regulation in the European Union, to analyse the way it has been implemented in Belgium so far, to consider the possible evolution of ATMP Regulation in Belgium and the perspectives of the healthcare biotechnology sector.
1. ATMPs in the European legislation
1.1 The birth of a new category of medicinal products
Scientific progress, specifically in the healthcare biotechnology sector, has rapidly given birth to products that had or could not have been taken into account when Directive 2001/83 was drafted. Directive 2003/63, amending Directive 2001/83 in order to include these new categories of biotechnological products4 introduced ATMPs in Part IV of Annex I of Directive 2001/83. It dealt with the specific requirements that should be met when seeking a marketing authorisations for such products.
A distinction was made between two different kinds of products: (i) gene therapy medicinal products; and (ii) somatic cell therapy medicinal products (both human and xenogeneic). Tissue-engineered products did not fall within the scope of those provisions but the ATMP Regulation is extended in order to cover them.
1.2 The donation, procurement and testing of human tissue and cells
Regulation 1394/2007 leaves Directive 2004/23/EC intact. This means that the phases of donation, procurement and testing of the human tissue and cells involved in the manufacture of ATMPs remain governed by the provisions of the Directive 2004/23/EC and its national implementing instruments.5
Directive 2004/23 requires Member States to designate a competent authority or authorities responsible for implementing the requirements of the Directive and for accrediting, designating, authorising or licensing the conditions under which procurement and testing are carried out. Moreover, Article 6(1) of the Directive adds that: "Member States shall ensure that all tissue establishments where activities of testing, processing, preservation, storage or distribution of human tissues and cells intended for human applications are undertaken have been accredited, designated, authorised or licensed by a competent authority for the purpose of those activities."
Those provisions left Member States room to manoeuvre in the regulation of tissue establishments.
1.3 The interaction between the ATMP Regulation and Directive 2004/23/EC
The interaction between the scope of application of the ATMP Regulation and the Directive can be illustrated as follows:
As the table shows, Directive 2004/23/EC applies to any human tissues and cells intended for human use. It does not apply to animal tissues and cells, or to human tissues or cells that are not intended for human use.
Moreover, the provisions of Directive 2004/23/EC do not apply to manufactured products derived from human tissues and cells and intended for human use that are governed by other European laws, except for the donation, procurement and testing of those human tissues and cells.
1.4 The ethical neutrality of ATMP Regulation
Article 28 of the Regulation provides for various modifications of Directive 2001/83, among which the addition of, a fifth paragraph in Article 4, which states that the Directive and all Regulations referred to therein shall not affect the application "of national legislation prohibiting or restricting the use of any specific type of human or animal cells, or the sale, supply or use of medicinal products containing, consisting of or derived from these cells, on grounds not dealt with in the aforementioned Community legislation (...)"
According to the preparatory documents, the aim of this article is to leave the ethical debates surrounding embryonic and umbilical cord blood tissues and cells to the respective Member States.
However, the wording of that new paragraph creates a risk regarding the possibility of maintaining or implementing national legislation, which would, on grounds not dealt with in the European legislation, prohibit or restrict the exercise of activities falling within the scope of ATMPs. Such a wide scope of interpretation in the hands of the Member States provides little by way of legal certainty in this regard.
Therefore, it is crucial to closely follow the status of the ethical debate surrounding biotechnology in the Member States in order to know if and to what extent those Member States will rely on this optout.
2. Belgian regulation
2.1 The state of implementation of the Directives in Belgium
The terms "medicinal product" and "substance" have the same definition in Belgian law as in European law, as the European definitions of those terms, provided by Directive 2001/83, can be found in the Law of 1 May 2006 revising the pharmaceutical legislation.
The provisions of Annex I of Directive 2001/83, as modified by Directive 2003/63, were implemented by the Royal Decree of 4 March 2004.
Directive 2004/23 has, however, not yet been implemented, although it should be by 7 April 2006.
2.2 The donation, procurement and testing of human tissue and cells
We have seen above that under the ATMP Regulation, the donation, procurement and testing of human tissue and cells will still fall within the scope of Directive 2004/23. The status of tissue banks is thus a crucial issue for the healthcare biotechnology sector.
Although Directive 2004/23 has not yet been implemented, regulations regarding tissue banks exist in Belgium. In a nutshell, the Royal Decree of 15 April 1988 provides a definition of a tissue bank which implies that such a tissue bank must be a unit of a hospital. Therefore, none of the aforementioned activities may be performed outside a hospital. The definition of the term "tissue" given by that Royal Decree is the following: "the tissues of human origin collected from a person with a view to using them as allograft with a therapeutic purpose on another person."
It is clear that the above text is out of date in light of the scientific progress made over the past twenty years. This is one of the factors that led to the publication of a new Royal Decree on 23 December 2002, which was annulled by a decision of the Council of State
As we have just seen, it is currently not possible for a biotechnology company to develop products consisting of human tissue or cells and put them on the market without being accredited as a tissue bank. As this accreditation is only granted to hospitals, the limitations are clear.
However, the Belgian regulation is likely to change, as the implementation of the Directive 2004/23/EC should occur in the near future. The crucial question is therefore to know what these changes will be.
The most recent law proposal implementing Directive 2004/23 was filed in December 2007. The provisions of that draft law propose a definition for tissue establishments which is very close to the definition provided by Directive 2004/23.
The proposal leaves the Crown the task of defining the requirements needed to obtain accreditation as a tissue establishment.
It must be stressed that the scope of application of the proposal is broader than the scope of the Directive, as it includes scientific research as such, though Directive 2004/23 only aims at scientific research in which a human application is intended.
The European Union is attempting to implement an open market for medicinal products in which standards of quality can be determined and controlled. However, the ATMP Regulation creates a risk for the biotechnology sector, as it leaves room for Member States to implement legislation which would prevent companies from putting ATMPs on the market, despite the EMEA marketing authorisation that would have presumably been granted to the product through the centralised procedure (mandatory for biotechnological products). This is the result of choosing an ethically neutral text. The potential problems that could arise from the current situation are linked to the complexity of the subject matter, as an individual type of, for example, stem cell, is distinct from any other, and so does not necessarily raise the same ethical questions.
It is not yet certain whether it will be possible, in the near future, for private companies to develop ATMPs without depending on hospitals. Moreover, it is not yet known if, in the short term, it will be possible for a private company even to sell ATMPs in Belgium.
Political choices will have to be made in this matter. The main concerns of the sector regard the donation, procurement and testing phases of their manufacturing processes. Parties operating in the sector are currently conducting a review about these issues, in order to determine if it will be possible for them in the future to obtain accreditation as tissue establishments. The healthcare biotechnology sector will undoubtedly look to the forthcoming regulations with keen interest.