In the European Union (E.U.), the European Commission first proposes legislative acts that the European Parliament can either adopt or amend. If the European Parliament decides to adopt the legislative act, it is sent directly to the European Council to be adopted as law. If the European Parliament disagrees with a proposed act, it must follow a procedure of amendments, votes and other negotiations before returning to Parliament and the Council for re-evaluation prior to becoming a law or legal act.
Legal acts in the E.U. can be divided into two categories: legally binding or non-legally binding. Regulations, directives and decisions are legally binding. Regulations are directly applicable to all Member States — or constituent countries — of the E.U. In contrast, directives must be adopted into national law. A Member State adopting a directive is free to change the format and content of the directive; however, the intended results of the directive must be achieved. The provisions laid out in directives are considered minimum requirements; and therefore a Member State may have more stringent requirements when it adopts a directive into national law. Recommendations and opinions are non-legally binding legal acts — recommendations are intended for all Member States, but adoption of the recommendations into national law is not required. Opinions are only applicable to the Member States specifically named within it.
Like the United States, the E.U. has adopted a tiered, risk-based approach to the regulation of cellular therapy products. The general quality and safety provisions covering the donation or procurement, testing, processing, preservation, storage and distribution of human cells and tissue are covered in two directives: Directive 2004/23/EC and Commission Directive 2006/17/EC. Higher risk cellular therapy products — also called advanced therapy medicinal products (ATMPs) — are regulated by the European Medicines Agency (EMA), which is responsible for the protection of public and animal health through the scientific evaluation and supervision of medicines in the E.U.; requirements for these products are included in Regulation (EC) 1394/2007. Brief summaries and highlights of cellular therapy-related directives and regulations in the E.U. are provided below.
Directive 2004/23/EC applies to hematopoietic peripheral blood, umbilical cord blood, and bone marrow stem cells, reproductive cells, fetal tissues and cells, and adult and embryonic stem cells and defines procedures for setting quality and safety standards for the procurement or donation, testing, processing, preservation, storage and distribution of human tissues and cells. This directive requires that Member States supervise the procurement of human cells and tissues as well as oversee the accreditation, designation or authorization of establishments that prepare and process tissues and cells. Generally, these activities are regulated at the Member State level by each country's respective National Competent Authority (NCA). NCAs also are responsible for inspecting establishments, verifying that appropriate control measures are in place for the procurement or donation process, ensuring that human tissues and cells are traceable from the donor to the recipient and vice versa, and establishing a donor identification system that assigns a unique code to each donation. Additionally, the requirements for importing and exporting human cells and tissues, maintaining a record of activities for each establishment, establishing a national registry of facilities, and reporting serious adverse events and reactions are included in this directive.
The selection and evaluation of prospective donors also are addressed in this directive — the requirement that Member States have procedures in place with respect to donor selection and evaluation, including consent, data protection and confidentiality, and the procurement or donation process. Member States also are required to ensure establishments have a quality management system, designate a responsible person to ensure compliance with this directive, and confirm personnel are qualified to perform their specified activities. Additionally, this directive addresses requirements for receipt, processing, storage conditions, labeling, packaging, and distribution of tissues and cells, as well as the documentation of these activities.
The specific requirements applicable to donation, procurement and testing of human cells and tissues are addressed in this 2006 directive. This directive requires that procurement be carried out by persons who have completed a successful training program and that establishments have standard operating procedures for verifying the donor's identity, obtaining consent or authorization, assessing donor eligibility based on specified selection criteria and assessing required laboratory tests. To maximize the safety of the procurement or donation of human tissues and cells, this directive also requires that these activities are performed in a facility that minimizes bacterial or other contamination and are undertaken in an environment that ensures the donor's health, safety and privacy, as well as requires that qualified sterile instruments and other devices are used.
The selection criteria for prospective living and deceased tissue and cell donors — except donors of reproductive cells — are covered in Annex I. These donors should be evaluated based upon an analysis of risks — derived from data from a physical examination, a review of medical and behavioral history attained through a questionnaire and an interview, biological testing, a post-mortem examination for deceased donors, and any other appropriate investigation — relative () to the intended use of the specific cells or tissues.
Generally, the same exclusion criteria apply to deceased and living donors; in the 2006 directive, these include, but are not limited to, a history of a disease with unknown etiology; history — or clinical or laboratory — evidence of HIV, acute or chronic hepatitis B — except in cases of a person with a proven immune status, hepatitis C, or HTLV I/II, or transmission risk or evidence of factors for these infections; recent history of vaccination with a live, attenuated virus where the risk of transmission is considered to exist; and transplantation with a xenograft. However, additional specific criteria may need to be added such as pregnancy, breastfeeding, and the potential — based on the tissue or cell to be donated — for transmission of inherited conditions for hematopoietic progenitor cell donors.
All tissue and cell donors — except donors of reproductive cells — must be tested for the following infectious diseases using methodology to identify the specified markers that were noted in Annex II:
|HIV 1 and 2||Anti-HIV 1 and 2|
|Hepatitis B||HBsAg, Anti-HBc|
|Syphilis||A validated testing algorithm should be applied to exclude the presence of Treponema pallidum|
*Additional notes regarding syphilis testing are provided in Annex II, 1.4.
Human T-lymphotropic virus-1 testing must be performed on donors living in, or originating from, high-incidence areas or who have sexual partners or parents originating from those areas. Furthermore, based on the donor's history and the characteristics of the tissues or cells, additional testing may be required for RhD, malaria, cytomegalovirus, Epstein-Barr virus, and Trypanosoma cruzi. All testing must be carried out by a qualified laboratory that is authorized as a testing center by the NCA in the Member State and testing must be performed using EC-marked and validated test kits.
Annex III of this directive covers the infectious disease testing requirements and selection criteria for reproductive tissues and cells for partner donation both for direct use and non-direct use, and donations from individuals other than partners.
The specific rules concerning the authorization, supervision, and pharmacovigilance requirements for ATMPs in the E.U. are addressed in this regulation. An ATMP may be a gene therapy medicinal product, somatic cell therapy medicinal product, tissue engineered product, or a combination of two or more of these products. Directive 2004/23/EC, as implemented by Commission Directive 2006/17/EC, also applies to the donation, procurement, and testing processes for an ATMP.
An ATMP must be approved using the Centralized Procedure, which is the regulatory pathway for submitting a Marketing Authorization Application (MAA), which is similar to a Biologics License Application or a New Drug Application in the US. An approved MAA allows a facility to distribute the newly-licensed product throughout the E.U. This regulation also outlines marketing authorization requirements which include donation or procurement processes, testing, clinical trials, good manufacturing practice and information related to medical devices. The specific requirements for the summary of product characteristics, labeling, and the package leaflet/insert also are covered in this regulation.
Once an ATMP has been approved, it is still subject to regulatory activities. For instance, a risk management system may be required to ensure the safety and effectiveness of the ATMP. Applicants also are required to report adverse events and reactions. ATMPs also must be traceable from the donor to the patient and vice versa. The regulation also lays down the provisions for the Committee for Advanced Therapies (CAT), a multidisciplinary group at the EMA responsible for assessing the quality, safety and efficacy of ATMPs. Additionally, the CAT's duties include preparing a draft opinion of a marketing authorization — granting, variation, suspension or revocation — on each ATMP application submitted to the EMA via the Centralized Procedure. The CAT also may draw up a scientific opinion on matters related to ATMPs if requested by the appropriate authority.
The manipulations that are considered substantial, and would qualify a product to be regulated as an ATMP, are listed in Annex I; these manipulations include cutting; grinding; shaping; centrifugation; soaking in antibiotic or antimicrobial solutions; sterilization; irradiation; cell separation, concentration or purification; filtering; lyophilization; freezing; cryopreservation; and vitrification. The specific requirements for the summary of product characteristics, which is the document describing the properties of the product that is made available to the public once it has been approved, is provided in Annex II. The requirements for the outer packaging labeling and the package leaflet are described in Annexes III and IV, respectively.