The European Commission's Directorate General for Enterprise (DG-Enterprise) works to "ensure all businesses compete and trade on fair and equal terms, that Europe is an attractive place to invest and work, and that growth is in knowledge-based and innovative industries." In the context of regulatory toxicology, DG-Enterprise is responsible for developing frameworks for the safety assessment and regulation of:
Pharmaceuticals
Responsibility for ensuring the safety and efficacy of medicinal products for human and veterinary use in the EU is shared between DG-Enterprise, which establishes pharmaceuticals policy and creates/maintains legislation, and the European Medicines Agency (EMEA), which provides scientific guidance and oversight to ensure consistency and compliance with legal requirements established by DG-Enterprise. A cornerstone of the EU legislative framework for pharmaceuticals is Regulation (EC) No 726/2004, which requires the authorization of all medicinal products marketed EU-wide, and establishes the EMEA Committees for Medicinal Products for Human and Veterinary Use (CHMP and CVMP, respectively), to review all applications for EU-level authorization and provide independent scientific advice on a variety of matters.
EU requirements for the safety assessment of medicinal products have been harmonized with those of other major pharmaceuticals markets (i.e., US and Japan) under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH), respectively. ICH guidelines for the safety assessment of human medicines call for a wide array of pre-clinical (animal) studies, followed by several phases of human clinical studies, before a new drug is deemed safe for marketing. Commonly required animal tests include the following:
- Toxicokinetics and pharmacokinetics in rodents and/or other species
- Single-dose studies in rodents, and occasionally dogs and primates
- Subacute (14-28 day), subchronic (90 day) and/or chronic (90+ day) studies in rodents, dogs, and occasionally primates
- Reproduction segment I––fertility studies in rodents
- Reproduction segment II––prenatal developmental toxicity in rodents and rabbits
- Reproduction segment III––postnatal development in rodents
- Mutagenicity and genotoxicity studies of at least 2 varieties
- Carcinogenicity studies in rats and transgenic mice
- Immunotoxicity in rodents
- Triggered specialized studies (e.g., phototoxicity, pyrogenicity, etc.)
Such testing consumes many thousands of animals, and is required for both the active medicinal ingredient(s) as well as each formulated drug product. Yet despite these costs, "a new [human] medicinal compound entering Phase 1 testing, often representing the culmination of upwards of a decade of preclinical screening and evaluation, is estimated to have only an 8 percent chance of reaching the market" (source). Such high failure rates have called into question the accuracy of animal studies in predicting human clinical outcomes and prompted calls for greater acceptance and use of alternative methods such as in vitro and "omic" techniques in preclinical safety testing, as well as alternative clinical approaches such as human microdosing.
Biologics
A complex framework of regulations and directives has been developed to control the marketing of biologics and other medicinal products intended for human or veterinary use. These include:
- Directive 65/65/EEC, which establishes a marketing authorization requirement for all medicinal products
- Regulations (EEC) No 2309/93 and (EC) No 726/2004, which lay down EU-wide authorization procedures and establish the European Medicines Agency
- Directives 2001/83/EC and 2003/63/EC, prescribing specific analytical, pharmacotoxicological and clinical standards and protocols for the testing of medicinal products for human use, and requiring compliance with the quality standards of the European Pharmacopoeia
Responsibility for ensuring the safety and effectiveness of medicinal products in the EU is shared between DG-Enterprise, which sets policy and creates/maintains legislation; the European Medicines Agency (EMEA), an independent agency that is responsible for pre- and post-market evaluations of medicinal products to ensure that they meet the safety, efficacy and quality requirements of EU legislation; and the European Directorate for Quality of Medicines & HealthCare (EDQM), a division of the Council of Europe, which develops binding monographs (published in the European Pharmacopoeia) to ensure appropriate quality control and quality assurance for medicinal products in the EU. EDQM also co-ordinates a network of quality-control laboratories throughout the EU.
Two procedures exist for the authorization of medicinal products:
- A decentralized system of national authorization and mutual recognition on other EU member states.
- A centralized procedure whereby an application for authorization is made directly to EMEA, reviewed either by the Committee for Human Medicinal Products' (CHMP) – possibly with input from its Biologics Working Party – and if endorsed, authorized by DG-Enterprise for marketing in all member states. All biotechnology-derived proteins, gene transfer products and recombinant virus vaccines are subject to review according to the centralized procedure.
EMEA guidelines and European Pharmacopeia monographs prescribe an extensive testing regime for vaccines and biologics to establish the following:
- Purity, meaning that it is not contaminated with viable bacteria, viruses or fungi.
- Safety, meaning that it is not dangerous or harmful. To this end, testing may be required for hazards such as pyrogenicity, neurovirulence, and other specific toxicities. Specific safety tests are also required during production of veterinary vaccines.
- Potency, meaning that it is effective in preventing infection. For live, attenuated vaccines, this may be determined by means of a "challenge study," in which groups of animals are first inoculated with a vaccine and are then exposed to a virulent strain(s) of the organism against which the vaccine is intended to protect. Animals are then monitored for clinical signs of the infectious disease in question, which may involve considerable pain, suffering, and ultimately, death. A less invasive alternative to challenge studies involves the measurement of serum titers in vaccinated animals.
In addition, vaccines are generally subject to years of human clinical or animal field trials to further evaluate their safety and efficacy. Furthermore, Directives 89/342/EEC and 89/381/EEC provide that "Member States shall take all appropriate steps to ensure that the manufacturing processes used in the manufacture of immunological products are properly validated and attain batch-to-batch consistency," including requiring companies "to submit samples from each batch of the bulk and/or finished product for examination by a State laboratory or a laboratory designated for that purpose before release on to the market…." Such batch testing is conducted by Official Medicines Control Laboratories (OMCLs) in EU member states, which interact closely with the EDQM.
It is estimated that approximately one-fifth of all EU animal use in toxicology occurs in the biologics sector. Relevant alternative methods validated to date include ELISA batch potency tests for erysipelas and human tetanus vaccines, the toxin binding inhibition (ToBI) test for human tetanus vaccine, and several others. Since 2005, EU regulators have also accepted that target-animal safety testing of veterinary vaccines can be waived if at least 10 consecutive batches comply with the test requirement.
Chemicals
In December 2006, the EU completely revised its regulatory framework for chemicals through passage of Regulation (EC) No 1907/2006 concerning the registration, evaluation, authorization and restriction of chemicals (REACH). Development of the REACH regulation was a joint effort by DG-Enterprise and DG-Environment to harmonize the regulatory frameworks for "new" and "existing" chemicals and to establish minimal information requirements for substances produced or marketed in the EU in volumes of one metric ton or more per year.
Under REACH, the regulatory functions currently performed by the European Chemicals Bureau will be subsumed under the new European Chemicals Agency (EChA). Animal testing requirements vary according to a chemical's annual production volume and the anticipated level of human and environmental exposure. Standard in vivo data requirements are as follows:
Annual production volume ≥ 1 ton:
- Skin sensitization in mice or guinea pigs
- Acute systemic toxicity by the oral route
- Mutagenicity, if in vitro test results are positive
Annual production volume ≥ 10 tons:
- All requirements listed above
- Eye irritation in rabbits
- Skin irritation in rabbits
- Acute systemic toxicity by a second route (inhalation or dermal)
- Further mutagenicity/genotoxicity, if triggered
- Subacute (28 day) or subchronic (90 day) toxicity in rodents
- Reproductive/developmental toxicity screening study in rodents
- Acute aquatic toxicity to fish
Annual production volume ≥ 100 tons:
- All requirements listed above
- Further mutagenicity/genotoxicity, if triggered
- Subchronic (90 day) or chronic (18-24 month) toxicity in rodents
- Prenatal developmental toxicity in one species
- Reproductive toxicity in 2 generations of rodents, if triggered
- Long-term aquatic toxicity to fish
- Aquatic bioaccumulation in fish
Annual production volume ≥ 1000 tons:
- All requirements listed above
- Prenatal developmental toxicity in a second species, if triggered
- Reproductive toxicity in 2 generations of rodents
- Carcinogenicity study in rodents
- Long-term or reproductive toxicity to birds
Estimates of potential vertebrate animal use to evaluate the approximately 30,000 chemicals that currently fall within the scope of REACH range from 8-9 million to as many as 45 million. Measures that have been built into the REACH regulation to minimize new animal testing include:
- The principle of "one substance, one registration," which requires manufacturers and downstream users to form consortia and share available toxicity data
- Opportunities to adapt or waive standard testing requirements under certain circumstances, including the use in vitro and other alternative methods at the level of prevalidation
- The requirement that companies submit proposals to the newly established Chemicals Agency for review, public comment, and approval before commencing new vertebrate testing for the two highest tiers of data requirements
In addition, the European Commission, in cooperation with Member States, the chemicals industry, and other stakeholders, has organized a number of REACH Implementation Projects (RIPs) to develop practical tools and guidance for industry and authorities, and also helped to coordinate the Strategic Partnership on REACH Testing (SPORT) as a pilot study to "test the workability of the REACH proposal, identify solutions where problems are found, feed solutions into the decision-making process and the [RIPs] and improve understanding of REACH."
REACH implementation will occur in several distinct phases, including a start-up period for the new Chemicals Agency, and three sets of statutory deadlines for chemical registration based on annual production volume. In addition, the Chemicals Agency will be responsible for revising REACH data requirements and EU test methods regulations as new alternative methods are validated and achieve regulatory acceptance.
Cosmetics
The sale of cosmetics in the EU is regulated under Directive 76/768/EEC, as amended, which stipulates that "[a] cosmetic product put on the market within the Community must not cause damage to human health when applied under normal or reasonably foreseeable conditions of use…." Toxicological testing requirements are not specified either for finished cosmetic products or their raw ingredients, although some chemical ingredients may fall within the scope of other regulations, such as REACH. However, the Commission's Scientific Committee on Consumer Products (SCCP) has published a set of guidance notes that recommend extensive toxicological testing of "new to the world" cosmetic ingredients, including the following types of studies:
- Acute systemic toxicity
- Eye and skin irritation
- Skin sensitization
- Skin absorption
- Phototoxicity
- Metabolism and toxicokinetics
- Subacute (28 day) and/or subchronic (90 day) toxicity
- Reproductive and developmental toxicity
- Mutagenicity and genotoxicity
- Carcinogenicity
In contrast to SCCP guidance, the European Parliament and Council have adopted a strong stance against animal testing of cosmetic products and their ingredients. Through the 7th Amendment to the Cosmetics Directive, the EU has moved toward banning:
- Animal testing of finished cosmetic products within the EU, as well as the marketing of cosmetic products and ingredients tested on animals outside the EU where "alternative" (including reduction/refinement) methods exist and are accepted in the EU, effective September 2004
- All animal testing of cosmetic ingredients within the EU, as well as the marketing of cosmetic products and ingredients using animals for all but the final four endpoints listed in Table 1, effective September 2009
- All cosmetic products and ingredients tested on animals for any purpose/endpoint, effective September 2013
Alternatives Policies & Actions
Directive 86/609/EEC regarding the protection of animals used for experimental and other scientific purposes stipulates that "[a]n experiment shall not be performed if another scientifically satisfactory method of obtaining the result sought, not entailing the use of an animal, is reasonably and practicably available," and further, "[i]n a choice between experiments, those which use the minimum number of animals, involve animals with the lowest degree of neurophysiological sensitivity, cause the least pain, suffering, distress or lasting harm and which are most likely to provide satisfactory results shall be selected." The 3Rs mandate imposed by Directive 86/609 applies to all Commission services, EU Member State authorities, and animal users throughout Europe. Accordingly, new and revised Community and Member State legislation must conform to the letter and spirit of this Directive.
Extramural funding for the development and validation of 3Rs methods is provided through the Research Framework Programs of DG-Research. As 3Rs methods are standardized and optimized, they may be eligible for pre-validation and validation in collaboration with the European Centre for the Validation of Alternative Methods (ECVAM), a division of DG-JRC. The results of validation studies may be subject to independent peer review by the ECVAM Scientific Advisory Committee (ESAC), and if endorsed, may be considered for regulatory acceptance at EU-level and/or internationally.
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