Regulatory Aspects for Adjuvants
Adjuvants alone are not licensed; a specific adjuvant/antigen formulation is licensed. This implies that the development of an adjuvant is strictly related to the antigen present in the specific formulation.
Vaccine regulatory procedures across the USA and Europe are not harmonized, and there is no mutual recognition of licensing or lot release, despite ongoing efforts by the regulatory authorities in the USA and the EU to look at harmonization. Regulatory authorities in both regions request license applicants to look at International Committee on Harmonization (ICH) guidelines, thus forming a partial basis for harmonization. The ICH, provides guidelines for human pharmaceuticals, including biological products. It was launched in 1990 to harmonize the regulatory authorities of Europe, Japan and the USA in the industry and scientific and technical aspects of product licensure. The objectives of harmonization are more economical use of human, animal and material resources, and avoidance of delays in licensing new medicines while considering safety of the public.[102] The Committee for Medicinal Products for Human Use of the EMA has published a guideline titled, 'Guideline on adjuvants in vaccines for human use'.[103] In particular, it has issued a regulatory note regarding use of adjuvants with immunopotentiating properties referred to as 'immunomodulators' in vaccines. In this note, it has been stated that adjuvants should be part of the formulation that is administered. An adjuvant is intended to help the immune response by a local, simultaneous and concomitant action with the antigen. Immunomodulators precondition the immune system in a more systemic way. Nevertheless, most of the principles of the guideline on adjuvants in vaccines for human use are also applicable to immunomodulators.[104]
The Center for Biologics Evaluation and Research (CBER) of the FDA is also developing a regulatory approach to vaccine adjuvants and adjuvanted preventive vaccines for infectious disease indications. CBER/FDA has observed a substantial increase in the number of pre-Investigational New Drug (IND) meeting requests and IND submissions for investigational biologics formulated with novel adjuvants over the past few years. One concern of CBER's Office of Vaccines Research and Review and of the FDA Critical Path Initiative is to focus on the scientific research regarding development of new technologies to assess the safety and effectiveness of novel adjuvants. There is a major difference in the organization of responsibilities for regulation and control of human and animal vaccine products between the USA and Europe. In the USA, the US Department of Agriculture regulates the veterinary vaccines, whereas human vaccines are regulated by the FDA. Each of these organizations have different regulations for product approval and release. However, in the EU, the EMA controls the production of both veterinary and human vaccines leading to a more linked and harmonized regulatory guidelines for veterinary and human vaccines.[102]
Because vaccines are administered to healthy individuals including infants and children and there are potential safety concerns with novel adjuvants, extensive preclinical safety studies of adjuvants and adjuvanted vaccines, including local reactogenicity and systemic toxicity testing are required. Successful nonclinical evaluation of vaccines, as described in The WHO Guideline,[105] is an important step before proceeding with clinical development. A general guidance for the preclinical safety testing of vaccines has been published by the Committee for Proprietary Medicinal Products (CPMP) at the EMA: 'Notes for Guidance on Preclinical Pharmacological and Toxicological Testing of Vaccines' (CPMP/SWP/465/95). Some of the principles outlined in the ICH guidance document 'Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals (CPMP/ICH/302/95)' can also be applied to the safety testing of vaccines, particularly recombinant protein and peptide-based vaccines. Some guidance is also provided for certain products such as influenza virus vaccines and smallpox vaccines. The CPMP has established a Vaccine Expert Group (VEG) which is the same as the Office of Vaccine Research and Review (OVRR) at the FDA. VEG oversees some of vaccine product-related issues including the development of novel adjuvants. Indeed this group has published a draft guidance document for the safety testing of novel adjuvants: 'Guideline on Adjuvants in Vaccines' (CPMP/VEG/17/03/04v5/consultation).[62]
Guidance on clinical data needed for the approval of seasonal inactivated influenza vaccines and pandemic influenza vaccines are also available. The added value of the adjuvant in the adjuvanted vaccine formulation in comparison with unadjuvanted forms of the vaccine should be demonstrated. Approaches to demonstrate the added value of a vaccine adjuvant for flu vaccines are described briefly in two FDA guidance documents.[106] Pandemic threats raise extraordinary challenges for vaccine formulation and manufacture. Some promising approaches may contribute to speed up response time and increase the number of available vaccine doses in a pandemic. The EMA has defined a regulatory procedure for approval of pre-pandemic vaccine manufacture based on substrains of avian influenza known to be infective for humans. The approval process can be shortened in cases where only slight modifications to the vaccines and manufacturing procedures are needed.[102]
The common attitude of all the regulatory systems regarding risk–benefit evaluation is to favor safety over efficacy. However, in high risk groups, such as patients with cancer and AIDS, an increased level of toxicity is acceptable if the benefit is significant.
Products that are eligible for emergency use are those that 'may be effective' in preventing serious or life-threatening disease. Currently, no US-licensed vaccine contains the adjuvants MF59 or AS03, however. It could be authorized for emergency use only.[107] Under section 564 the Commissioner may establish conditions of authorization. These conditions include but are not limited to: requirements for information dissemination to healthcare providers; adverse event monitoring and reporting; data collection and analysis; and restrictions on product advertising, distribution and administration.
Expert Rev Vaccines. 2011;10(7):1053-1061. © 2011 Expert Reviews Ltd.
Cite this: Current Adjuvants and New Perspectives in Vaccine Formulation - Medscape - Jul 01, 2011.
