15 December 2009
IPSEN'S WORK ON DEVELOPING AN ALTERNATIVE TO ANIMAL TESTING FOR BOTULINUM TOXIN PRODUCTS
Overview
Currently, the mouse LD50 potency assay is the only method approved by regulatory authorities, anywhere in the world, to fully establish the potency of licensed medicinal botulinum toxin type A products. This test is therefore mandatory and pharmaceutical companies have no choice but to comply with the regulations.
Ipsen has been intensively searching for alternatives to animal testing for over seven years and will continue to do so until a method that meets the standards of quality, safety and efficacy required by both the company and the authorities is found.
Ipsen's botulinum toxin type A
Type A botulinum toxin has become the treatment of choice for a range of debilitating neuromuscular diseases. Botulinum toxin products are licensed as prescription-only medicines by the health authorities of each country in which they are approved. Ipsen botulinum toxin type A, Dysport®, was initially developed for the treatment of movement disorders together with various forms of muscular spasticity (including cervical dystonia) and later for the treatment of other neuromuscular disorders, and in aesthetic medicine. These treatments require highly controlled, quality medicinal type A botulinum toxin that meets the most stringent health care requirements. When the potency of the drug is clearly established, the risk benefit for the administration of the drug depends on accurately knowing the correct dose.
Whatever their uses and indications, botulinum toxin drugs remain prescription drugs and never qualify as "cosmetics".
Three Rs programme
Ipsen is committed to the 'Three Rs' principle of Refinement, Reduction and Replacement of laboratory animals used in the testing of botulinum toxin. The Company has made a continued and sustained effort in this area over many years. Ipsen has had significant success in refining the test and reducing the number of animals used for toxin testing. This reduction can only be made with the agreement of the regulatory authorities, and we continue this dialogue with the regulatory authorities and their representatives to ensure progress in this key area. Ipsen has been working for several years on replacements for the LD50 test for botulinum toxin which will continue to meet the standards of quality, safety and efficacy required by the company and the regulatory authorities. Dr Donald W. Straughan, a highly respected expert in the field of animal testing and, in particular, the testing of botulinum toxin products, reviewed the progress of this Ipsen research in the June 2006 issue of Alternatives To Laboratory Animals.1 Work has continued, and our replacement research is currently focused on a number of alternative testing methods; such as endopeptidase activity assays (including SNAP-25), enzyme-linked immunosorbent assays (ELISA) and assays which measure the binding capability of the product to the neuromuscular junction target. Such research is governed by the importance of establishing the exact potency of all batches using standardised methodology because such potency will determine the precise efficacy and safety of each injection, to guarantee patient safety.
As of today, no alternative assay method has ever been approved by any regulatory authority for the potency testing of licensed medicinal botulinum toxin type A products. Contrary to statements that were posted on the Internet, the SNAP-25 assay method developed by the UK National Institute for Biological Standards and Control (NIBSC) for specific internal use, has never been accepted for product quality testing and release by any regulatory authority in the world, since it only measures one property of botulinum toxin.
Recently, Ipsen has been an active part of a European initiative, sponsored by the German ZEBET/BfR institutes (dedicated to alternatives to the use of animals in many areas) which has been comprehensively reviewing the available alternative assay technologies. The inaugural meeting of the initiative was held in April, 2009 and the summary of the discussions held was reported by BfR to the 7th World Congress on Alternatives to Animals, held in Rome in July 2009. A detailed report of the first meeting will be published.
As a consequence of this initiative, a European Expert Working Group (EWG) on the replacement of the LD50 mouse potency test has been established. The detailed remit of the EWG is being established, and will be communicated when available. Members are manufacturers (including Ipsen), scientists and key European regulatory authorities. The group will fully review the situation and define clear paths forward towards replacements. This collaborative work is the most appropriate route ahead towards defining replacement of the assay, given the considerable scientific issues that must be addressed, to ensure the safety and efficacy of the products marketed and to satisfy the licensing authorities who must, under all circumstances, entirely accept any proposed changes.
This statement will be updated in the light of new developments in both the science and the EWG initiative, as progress is made within the industry towards a replacement method.
Reference
1. Straughan, DW. Progress in applying the three Rs to the potency testing of botulinum toxin type A. Alternatives To Laboratory Animals 2006; 34(3):305-313
