March 26, 2009
Q&A: EU Testing of Vaccines
Q: What are vaccines?
A: Vaccines are a class of immunological medicinal products, or “biologics,” derived from living organisms.
Q: Who are the major European vaccines manufacturers?
A: Lead vaccine manufacturers include AstraZeneca, GlaxoSmithKline, Novartis, and Sanofi-Aventis.
Q: How are vaccines 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 vaccines and biologics?
- Purity, meaning that it is not contaminated with viable bacteria, viruses or fungi.
- Safety, meaning that it is not dangerous or harmful—which may be determined by means of “abnormal toxicity” or similar studies, in which groups of animals are injected with a vaccine and monitored for clinical signs of toxicity.
- Potency, meaning that it is effective in preventing infection—which is usually 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.
In addition, vaccines intended for use in humans are generally subject to years of human clinical 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.
Q: How many animals are used in the testing of vaccines?
A: 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 risks to people?
A: Not necessarily. In fact, some vaccines have been causally linked to severe adverse reactions in humans (e.g., anaphylactic shock brought on by hepatitis B vaccine; poliomyelitis in a contact of someone who received the oral polio vaccine; arthritis in recipients of the rubella vaccine; death in some recipients of the measles vaccine). 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: Relevant alternative methods validated to date include enzyme-linked immunosorbent assay (ELISA) batch potency tests for erysipelas [PDF] and human tetanus [PDF] vaccines, as well as a toxin binding inhibition test [PDF] for human tetanus vaccine. The ECVAM Scientific Advisory Committee has also issued a statement [PDF] calling for an end to target-animal safety test for batch safety testing of vaccines for veterinary use.
Q: What is HSI Europe doing to help animals used in vaccine 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.