However, these studies are subject to several methodological limitations, including sample size, the limited ability to detect adverse events, loss to follow-up, exemption of vaccine recipients with previous adverse events, observational bias, and the absence of unvaccinated control groups.By 2000, some 425,976 US service members had received 1,620,793 doses of AVA. The IOM review (2000-2004)
In October 2000, a committee of the Institute of Medicine (IOM) of the National Academy of Sciences was asked by the US Congress to review AVA according to the best available evidence. It issued its study in March 2002. The IOM panel noted that human data on inhalational anthrax prevention is limited due to the natural low incidence of disease and that therefore animal model data are the best we are ever likely to have. Primates and rabbits were considered the best models for human disease. As regards vaccine effectiveness, "The committee finds that the available evidence from studies with humans and animals, coupled with reasonable assumptions of analogy, show that AVA as licensed is an effective vaccine for the protection of humans against anthrax, including inhalational anthrax, caused by all known or plausible engineered strains of B. anthracis." With regard to safety, "The committee found no evidence that people face an increased risk of experiencing life-threatening or permanently disabling adverse events immediately after receiving AVA, when compared with the general population.
Licensure and limited occupational use (1970-1991)
In 1970, AVA was first licensed by the USPHS for protection against cutaneous anthrax to a state-owned facility operated by the Michigan Department of Public Health. In 1973, the US Food and Drug Administration (FDA) first published standards for making, using and storing AVA. In the mid-1980s, the FDA approved it specifically for two limited preventive indications: 1) individuals who may come in contact with animal products or high-risk persons such as veterinarians and others handling potentially infected animals; and 2) individuals engaged in diagnostic or investigational activities involving anthrax spores. In 1985, the FDA published a Proposed Rule for a specific product review of the AVA, stating that the vaccines "efficacy against inhalation anthrax is not well documented" (a statement quoted controversially many years later). For many years, AVA was a little known product considered to be safe for pre-exposure use in the US in at-risk veterinarians, laboratory workers, livestock handlers, and textile plant workers who process animal hair. In 1990, the State of Michigan changed the name of its original production plant facility to the Michigan Biologic Products Institute (MBPI) as it gave up state ownership and converted it to a private entity.