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March 25, 2009

Q&A: EU Testing of Pharmaceuticals

Humane Society International/Europe

For every drug and pharmaceutical product on the EU market, many thousands of animals have suffered and died in laboratory poisoning tests.

Q: What substances are considered pharmaceuticals?

A: Pharmaceuticals are a class of medicinal product that includes drugs, antibiotics, steroids and anesthetics. The term pharmaceutical does not include products derived from living organisms, such as vaccines and serums, or medical devices such as dental implants or heart valves.

Q: Who are the major pharmaceutical manufacturers in Europe?

A: Among the largest EU pharmaceutical companies are Akzo Nobel Pharma, AstraZeneca, Bayer HealthCare, GlaxoSmithKline, Merck, Novartis, Novo Nordisk, Pierre Fabre, Proctor & Gamble Pharmaceuticals, Roche, and sanofi-aventis. Many of these companies are members of the EU-level lobby group, European Federation of Pharmaceutical Industry Association.

Q: How are pharmaceuticals regulated in the EU?

A: A complex framework of regulations and directives has been developed to control the marketing of pharmaceuticals and other medicinal products intended for human or veterinary use. These include:

  • Directive 65/65/EEC [PDF], which establishes a marketing authorisation requirement for all medicinal products
  • Regulations (EEC) No 2309/93 [PDF] and (EC) No 726/2004 [PDF], which lay down EU-wide authorisation procedures and establish the European Medicines Agency
  • Directives 2001/83/EC [PDF] and 2003/63/EC [PDF], 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 medicinal products in the EU is shared between the European Commission Directorate General for Enterprise and Industry, 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 authorisation of medicinal products:

  • A decentralised system of national authorisation and mutual recognition on other EU member states.
  • A centralised procedure whereby an application for authorisation is made directly to EMEA, reviewed either by the Committee for Human (or Veterinary) Medicinal Products' (CHMP and CVMP, respectively), and if endorsed, authorised by DG-Enterprise for marketing in all member states. All biotechnology-derived proteins, gene transfer products, and other innovative medicines are subject to review according to the centralised procedure.

Q: What animal tests are carried out on pharmaceuticals?

A: EU testing requirements for human and veterinary pharmaceuticals have largely been harmonised with those of other major markets (i.e., the United States and Japan) under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and the International Co-operation on Harmonisation of Technical Requirements for Registration of Veterinary Products (VICH), respectively. Both entities publish guidelines specifying trilaterally agreed-upon methods for assessing safety, effectiveness and quality of pharmaceutical products. ICH guidelines 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. VICH guidelines likewise prescribe a significant battery of conventional toxicology studies, but also provide for evaluations of target animal and environmental safety, since a major use of veterinary drugs is in farmed animals.

Animal tests common to both ICH and VICH schemes include the following:

  • Absorption, distribution, metablolism and elimination studies in rodents and/or other species
  • 3 month repeated-dose general toxicity studies in rodents, dogs, and sometimes primates
  • 12-24 month repeated-dose general toxicity studies in rodents, dogs, and sometimes primates
  • Lifetime (18-24 month) cancer studies in rats and mice (ICH allows for the substitution of the 18-month mouse study with a shorter test in transgenic mice)
  • Genetic toxicity studies of at least 2 varieties
  • Reproductive toxicity study in at least 2 generations of rodents (ICH allows for this to be broken into separate adult fertility and post-natal segments in the context of a 1-generation study design)
  • Pre-natal developmental toxicity in rodents and rabbits
  • Immunotoxicity in rodents

In addition to the “core battery” above, national regulators and quality-control bodies known as Pharmacopoeias impose additional testing requirements on a case-by-case basis. For example, medicated skin creams are often tested in the presence of UV light to be sure they do not foster sunlight-induced “photo”-toxicity, while drugs administered intravenously must be specially tested to ensure that they are not contaminated with fever-causing “pyrogens.”

Q: How many animals are used to evaluate pharmaceutical safety and effectiveness?

A: Some of the tests above consume hundreds or thousands of animals per study, and such testing is typically required for both the active medicinal ingredient(s) as well as each formulated pharmaceutical product (and sometimes for each new batch of a product). In 2005, tests for the “production and quality control of products for human medicine and dentistry and for veterinary medicine” consumed 1,854,553 animals, or approximately 15.3 percent of all animals used for all experimental purposes in the EU, according to European Commission statistics [PDF]. (It is not possible at this time to distinguish between animal use in the pharmaceutical vs. vaccine/biologics sectors.)

Q: Are animal tests accurate predictors of potential adverse drug reactions in people?

A: Not necessarily, as catastrophic drug failures—such as the recent TGN 1412 incident in the United Kingdom—have revealed. In fact, the World Health Organisation reports that in some countries, adverse drug reactions are responsible for upwards of 10 percent of all hospital admissions. And according to the US Food and Drug Administration, “a new 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” because animal studies so often “fail to predict the specific safety problem that ultimately halts development.” 

Q: What are the alternatives?

A: A number of in vitro and other alternative methods germane to pharmaceutical safety and quality assessment have been endorsed as scientifically valid by the European Centre for the Validation of Alternative Methods (ECVAM) and its counterparts worldwide for endpoints including skin and eye irritation, sunlight-induced “photo”-toxicity, genetic toxicity, fever-inducing “pyrogenicity,” toxicity to the developing embryo, and toxicity to the blood.

In addition, an expert group comprised of 15 international pharmaceutical companies and contract testing facilities, together with the UK National Centre for the 3Rs, has recently concluded that “the information obtained from conventional acute toxicity studies is of little or no value in the pharmaceutical development process,” and has recommended that single-dose acute systemic toxicity studies be dropped from ICH and related national guidelines for human pharmaceuticals.

Another innovative technique with the potential to not only reduce animal use, but also to obtain much more relevant and meaningful scientific information, is called microdosing [PDF]. By administering a very small dose of a candidate drug to healthy human volunteers, important human-specific information can be obtained, without the uncertainties associated with extrapolating test results from one species to another.

Q: What is HSI Europe doing to help animals used in pharmaceuticals testing?

A: HSI Europe has been at the forefront of lobbying efforts to ensure that all available, validated non-animal methods and testing strategies achieve expeditious regulatory acceptance in the EU. Additionally, HSI Europe and affiliate organisations The Humane Society of the United States (HSUS) and Humane Society Legislative Fund have assumed a leading role in supporting implementation of the vision of “twenty-first century toxicology” articulated by the U.S. National Research Council, which would see animal tests that are decades old, costly, slow and of dubious relevance to people replaced by ultra-modern, efficient and human-relevant non-animal methods. HSI Europe is calling for a “big biology” project to meet this challenge, akin to the Human Genome Project of the 1990s, and are forging an international, multi-stakeholder consortium make this landmark vision a reality as quickly as possible. 

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