Advanced therapies

Advanced therapies – gene therapy, somatic cell therapy and human tissue engineering – are new approaches of modern medicine that are expected to result in revolutionary treatments to a number of diseases and injuries.

What is tissue engineering?

Tissue engineering is the design, specification and fabrication of cells, biomaterials or biomolecules to restore or modify the biological functions of tissues. Products currently on the market include simple tissue products such as skin, cartilage and bone but the technology could lead to the in vitro construction of human organs. Human tissue engineering differs from standard therapies in that the engineered products grow with the patient and become a part of their body. 

Tissue engineering is an emerging area and no clear boundaries exist so far between tissue engineering and certain other allied areas, which will result in inevitable overlaps with other forms of treatment. A definition, therefore, is essential to provide a sound basis for demarcation between tissue engineered products on the one hand and medical devices, pharmaceutical products and cell therapy on the other.

In June 2000, when the Directive concerning medical devices incorporating derivatives of human blood and plasma (modifying Directive 93/42/EEC of  June 1993 concerning medical devices) was adopted, the Council and Commission agreed that devices incorporating other derivatives of human tissues should be subject to specific legislation. The Commission's Scientific Committee on Medicinal Products and Medical Devices issued an opinion on the state of the art concerning tissue engineering in 2001.

What are advanced therapies?

Three kinds of advanced therapies - gene therapy, somatic cell therapy, and human tissue engineering - are expected to change medical practice significantly. They are based on complex, highly innovative manufacturing processes aiming at modifying genetic, physiological or structural properties of cells and tissues. The specificity of the product lies in the process. 

The current lack of an EU-wide framework leads to divergent national approaches as to the legal classification and authorisation of advanced therapy products, which ultimately negatively affects the EU’s innovative capacity and competitiveness in this key area of biotechnology. 

The Commission carried out stakeholder consultations on the issue in 2002 and 2004. The results of these consultations led to a draft  regulation and a consultation paper on a proposed regulatory framework which were published for public comment in May 2005.

Regulation on advanced therapies

Three kinds of advanced therapies - gene therapy, somatic cell therapy, and human tissue engineering - are expected to change medical practice significantly. They are based on complex, highly innovative manufacturing processes aiming at modifying genetic, physiological or structural properties of cells and tissues. The specificity of the product lies in the process. 

Following a stakeholder consultation on the regulation of the advanced therapies, the Commission published its official proposal on the issue in November 2005. The main elements of the proposed framework for advanced therapies are: 

  • a centralised marketing authorisation procedure, to harmonise and facilitate access to the EU market;
  • a new expert committee for advanced therapies, within the European Medicines Agency (EMEA) to assess advanced therapy products; 
  • new, tailor-made technical requirements for advanced therapy products; 
  • strengthened risk management and traceability requirements; 
  • special incentives for small and medium-sized enterprises (SMEs).  

The Commission thinks that human tissue- and cell- based products should be founded on the philosophy of voluntary and unpaid donation, anonymity of both donor and recipient, altruism of the donor and solidarity between donor and recipient. 

As to the ethical aspects, the proposal respects national competence as regards the use of for example embryonic stem cells. In accordance with the subsidiarity principle decisions on such use or non-use remain a national responsibility.

In a public hearing on the regulation, on 11 May 2006, a Commission official summarised the Commission priorities concerning the regulation as follows:

  • assuring safe access to patients to new treatments,
  • competitiveness (supporting industry, SMEs),
  • subsidiarity/ethics.

Safety standards

Increasing number of patients throughout the EU undergo some form of therapeutic treatment based on the use of human tissue and cells, therefore it was recognised that EU-wide rules on quality and safety standards were necessary.

In June 2002, the Commission  proposed a directive on setting standards of quality and safety for the donation, procurement, testing, processing, storage and distribution of human tissues and cells. The proposal was successful and the new Directive was adopted in March 2004.  It covers all human cells and tissues which are used for application in the human body but it excludes blood and blood products (already regulated under EU law), human organs and any organs, tissues or cells of animal origin. Only human tissue provided by a donor is covered. 

The new Directive, transposed by the member states by April 2006, provides:

  • the establishment of a register of the entities operating in this field across the EU;
  • minimum quality and safety systems;
  • professional requirements and training necessary;
  • provisions for inspections and penalties in the member states;
  • mandatory minimum standards and procedures for the donation, testing, procurement, processing, storage, distribution and preservation of tissues and cells.  


Proposal for a regulation for a community regulatory framework on advanced therapies:
 

The industry welcomes the Commission's proposal as it lays down "the long-awaited harmonized rules for the approval and marketing of human tissue engineered products in the EU". 

EuropaBio, the voice of European Bioindustries: "The industry welcomes the choice of the Commission to opt for a Regulation in this field rather than a Directive to ensure that optimal and harmonised standards are used wherever a company or patient may be based in Europe."

"Europe is already late in this field yet has very promising technologies to offer. The US has had rules in place for these products for some time, but the field is changing continuously. US companies have benefited from a more predictable legislative environment and clarity. Predictability and clarity are two elements that are very important for companies to find investors prepared to invest in this research," said EuropaBio’s Secretary General Johan Vanhemelrijck. 

Eucomed, the European Medical Technology Industry Association,  the European association representing the majority of companies active in human tissue engineering in the EU strongly supports a harmonized framework for advanced therapies but "we need to be sure it fully takes account of the specific nature of human tissue engineered products which are neither pharmaceutical products nor medical devices," said the Director General of Eucomed Maurice Wagner. 

According to the proposed Regulation, countries retain the right to establish national ethical standards. Eucomed thinks that, "while this is understandable, the Regulation should require that member states be transparent and give notice of the human or animal cells that will be prohibited on their territory."

Eurordis, the European Organisation for Rare Diseases, has some reservations concerning the proposed Risk Management System, as it fears that the system may generate too many additional regulatory constraints.

For stakeholder reactions to the Commission's consultation, click here.

Directive 
EC/2004/23
on the safety and quality aspects of dealing with human tissues and cells:

Europabio response to the consultation largely welcomes the Commission proposal to use the pharma rules and aligns both the Medical Device and the pharma associations together. 

In its response to the consultation called by DG Enterprise, the Standing Committee of European Doctors (CPME) warns that it is important to strictly regulate the conditions of taking tissue samples. In the EU, original samples can only come from donations, which can either be taken from cadavers or from a living person, with the information and consent of the person or their legal successor. The conditions in which the samples are stored after distribution and sale to laboratories or enterprises that process these samples must be specified. Strict measures must be taken to avoid the risk of transmitting undesirable biological agents. To ensure that products, which are the outcome of these industrial procedures are made accessible to all European citizens, distribution inside as well as outside the EU must be regulated. 

The European Organisation for Rare Disorders (Eurordis) welcomes efforts to harmonise the use of human tissues and cells across the European Union, which will serve to facilitate and accelerate the development and use of new therapies for all diseases. At present, a significant gap exists among the different EU countries as regards the attention and sensitivity to this rapidly growing field of medicine. Since rare disorder patients are, by definition, isolated and geographically scattered, an EU-wide legislation could facilitate the access of all patients to the new tissue-engineered products. Eurordis already supports European harmonisation in this field by coordinating a European network of biological material banks (EuroBioBank), specialised in the collection of DNA, tissues and cells from patients affected by rare diseases.

The European Society of Cataract and Refractive Surgeons (ESCRS) welcomed the Directive under discussion on the standards and quality and safety of handling human tissues as it was drafted following consultations with such groups as the European Eye Bank Association. The new proposals will affect the ESCRS as it regulates the harvesting, testing and transplant of tissues, including eye tissues. In particular, the ESCRS points out that the new Directive will mandate ophthalmologists (medical scientists dealing with the structure, functions, and diseases of the eye) to import eye tissue through an accredited EU eye bank from a country whose tissue donation standards conform to those of the EU, as opposed to the current practice of ordering them directly.

  • The Council finally adopted the regulation (compromise package adopted by the Parliament on 25 April 2007) on advanced therapies on 31 May 2007.
  • The Parliament adopted, on 25 April 2007, the amended report by Miroslav Mikolášik on the Commission proposal (November 2005) for a regulation on advanced therapies. The MEPs rejected all ethical amendments proposed to the report.
  • An informal trialogue between the Commission, the Parliament and the Council (early 2007) aimed for adoption of the dossier in the first reading in the Parliament. The dialogue was interrupted by the Parliament's rapporteur, who insisted on inclusion of ethical amendments into the compromise proposal.
  • Due to controversy on inclusion of ethical amendments to the report, the EP's ENVI committee rejected the committee's first draft report (see draft report and amendments) in September 2006. A new report rejecting the ethical amendments was finally adopted on 30 January 2007.
  • Directive EC/2004/23 on the safety and quality aspects of dealing with human tissues and cells came into force in April 2004. Its provisions needed to be transposed by the member states by April 2006. The Commission has already adopted two sets of technical rules to help implement the legislation.

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