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Antivenom Risk-Benefit Assessment Procedure

Antivenom Risk-Benefit Assessment Procedure

Manufacturers who wish to apply for risk-benefit assessment must submit to WHO a detailed product dossier addressing terms of reference for a specified call for applications. The dossiers will be reviewed by a group of experts, and in parallel samples of the immunizing venoms, and the antivenoms themselves, will be subjected to robust laboratory analysis. WHO will also undertake inspections of manufacturing sites to verify adherence to Good Manufacturing Practices (GMP). Products which are found by WHO to be acceptable on the balance of the overall evaluation of risk-benefit may be recommended by WHO for procurement.

Dossier Review

A joint desk review assessment will be conducted by a Technical Advisory Group for Snake Antivenom Immunoglobulin Listing (TAG-SAIL) which may include international regulatory, veterinary, biologicals manufacturing, quality control, herpetological and medical experts. Regulators from the countries where the antivenoms are manufactured and marketed are invited to join this group. Using information and data provided by the relevant manufacturers, the group of experts will assign a risk‒benefit ratio to each product assessed.

Laboratory Assessment

In parallel a comprehensive physicochemical, analytical, and biological laboratory assessment is undertaken for each product. The quality, potency and biological activities of the venoms used to raise the antivenom are examined along with venoms from other geographical regions throughout the range of each immunizing species. Venoms of other medically important snake species are also included in the assessment to determine the extent of any broader paraspecific coverage that products may provide. The antivenoms are evaluated against each of the venoms using a combination of in vitro and in vivo quality control and preclinical efficacy assays in accordance with recommendations in the WHO Guidelines for the Production, Control and Regulation of Snake Antivenom Immunoglobulins.

GMP Inspections

WHO will conduct inspections of venom production facilities, small and large animal facilities, manufacturing and quality control facilities are part of a detailed evaluation of GMP compliance. Where deviations from GMP are identified manufacturers will be required to address these through a Corrective and Preventative Action (CAPA) process to the satisfaction of the WHO Prequalification Unit Inspection Services. Where GMP adherence is verified, manufacturers will receive a formal closure notice indicating that the relevant sites be considered compliant with GMP as published by WHO for the specific activities related to the manufacturing and quality control of the product.

Final Review

All the findings will be subject to final review by the dossier review panel to determine if on balance they demonstrate a reasonable likelihood that the quality, safety, and efficacy of the product are acceptable, and that, when used to treat snake bite in the countries in which it is marketed, its benefits will outweigh any foreseeable risks and uncertainties associated with its use.

Antivenoms with a positive risk-benefit ratio will be entered into a list on the WHO website, where information can be accessed readily by procurement agencies and other relevant parties. Where a product is excluded from the risk-benefit assessment due to any unsatisfactory finding, failure, or other deficiency, WHO will also publish the finding on the WHO website. Public Risk-Benefit Assessment Reports and Public GMP Inspection Reports for all the products assessed with also be published by WHO on the WHO website.