WHO has a constitutional responsibility to its Member States to develop norms and standards for vaccines and other biologicals, and regulatory issues are central to this mandate. As part of ongoing collaboration between WHO and UNAIDS to promote the development, evaluation and future availability of HIV vaccines, a consultation was organized by the WHO-UNAIDS HIV Vaccine Initiative in Geneva. The meeting was attended by 34 experts from 16 countries, and included representatives from governments, academic institutions, industry and international organizations*.

* Scientific Considerations for the Evaluation of HIV Vaccines and Related Regulatory Perspectives. WHO, Geneva, 13 - 16 March 2001. Organized by Quality Assurance and Safety of Biologicals, Department of Vaccines and Biologicals, WHO, and the WHO-UNAIDS HIV Vaccine Initiative.

HIV vaccine efficacy can be measured by prevention of infection and/or reduction of viral load or transmissibility. In order to give meaningful results and ensure the reliability and comparability of data, laboratory methods to measure potential correlates of protection need to be standardized through the development of relevant reference materials. The need for developing a coordinated international approach to assure the standardization, quality, safety and efficacy of HIV vaccines is essential and this process should involve regulatory scientists from both developed and developing countries (1).

The following priorities were identified during the meeting.

Standardization and control of HIV vaccines

• A thorough review of current guidelines and related documents should be undertaken to compare existing material for completeness and consistency.

• WHO should continue to disseminate and make widely available related information and documents, including the report of the meeting (2).

• A forum for experts should be established to provide advice to countries that need to develop or strengthen their national regulatory authorities.

• General or specific guidelines on viral and bacterial vectored vaccines for prophylactic use should be developed. Further research on vaccine potency must be supported.

• Regulatory research should be promoted to facilitate the development of further guidelines on cell substrate issues as they pertain to HIV vaccines.

• Consensus should be sought on methods to determine serological and cellular immune responses and viral load.

• Appropriate reference reagents should be prepared for standardized immunological and virological assays.

• Further development of the WHO - UNAIDS Network for HIV Isolation and Characterization should be sustained in response to the continued spread of HIV. The timely dissemination of molecular, biological and immunological information of incident viruses is essential.

Clinical evaluation of HIV vaccines

• HIV vaccine trials should be conducted only in countries with adequate regulatory control, and specific plans for strengthening should be made where regulatory resources are limited.

• It is essential that trials are performed with strong political and community support.

• Clinical trial designs should be based on clearly defined end points for vaccine efficacy and on their utility in relation to public health needs.

• Adequate clinical trial infrastructures should be put in place, including training of personnel in good clinical practice (GCP) procedures and monitoring.

• A set of criteria for moving HIV vaccine candidates to different stages of clinical trials in different target populations were formulated (for later publication).

• Proposals were made to strengthen national regulatory authorities and to identify approaches to regulatory harmonization on a regional and global level.

Facilitating regulatory approval

The regulatory oversight process spans the whole life-cycle of a vaccine, from the earliest development stages throughout production and use. Since there are differing approaches, criteria, standards, capabilities and timeliness in regulatory processes in different countries, these can produce delays in product availability because of varying scientific or application dossier requirements. This disharmony among regulatory systems has an additional inconvenience in the case of HIV vaccines because a number of candidates in early development utilize new technologies for which international consensus on safety and quality assessment is currently lacking.

Now that several novel candidate HIV-vaccines are becoming available for clinical trial study, it is important to consider generic regulatory issues regarding these products. Scientific criteria for assessing the safety, efficacy and quality of different types of candidate vaccines, especially those derived from novel biotechnologies, were considered, and a need for regulatory research concerning the type of product was identified.

Continuous and intensive exchange among national regulatory agencies and researchers should begin immediately on the scientific criteria for assessing the safety, efficacy and quality of potential candidate HIV vaccines, especially those derived from new technologies. A mechanism should be developed to facilitate timely agreement on clinical trial design (including efficacy endpoints and safety monitoring). This mechanism should allow for the need on occasion to update consensus on such questions. Developing country regulators and industry should be included from the beginning in this regulatory dialogue. The process must include provisions for information sharing between regulatory bodies as well as stringent and meaningful confidentiality protection.

More dialogue among regional officials and NRAs should be supported and encouraged. This should include sharing national HIV vaccine plans, which ideally should be part of a regional HIV plan. For those countries with minimal resources for NRAs, WHO could play an important facilitator role to obtain outside expert advice on a case-by-case basis, for both the investigational and licensing stages. Consideration should be given to the establishment of an international regulatory reference group convened by WHO, which can advise and support countries as needed.

International and national support should be directed toward developing countries for the specific purpose of strengthening regulatory expertise and building infrastructure in sufficient time to facilitate swift approval of safe, effective vaccines - particularly those for life-threatening diseases. Additional funding is also needed to enable WHO to assist developing countries to develop consensus on safety, quality and efficacy issues as well as to review vaccine candidates derived by novel technologies or biotechnologies.

Reference

1. Approaches to the development of broadly protective HIV vaccines: challenges posed by the genetic, biological and antigenic variability of HIV-1. Report from a meeting of the WHO-UNAIDS Vaccine Advisory Committee, Geneva, 21-23 February 2000. AIDS, 15: W1-W25. (2001).