US President Clinton and top federal officials have designated bioterrorism preparedness a major priority. In doing so, they plan to stockpile certain vaccines and antimicrobial drugs—a step that very much depends on improving and, in some cases, replacing specific components that are to make up that stockpile. Evaluating vaccines to protect against bioterrorist-inflicted diseases presents unusual challenges. Consequently, officials at the US Food and Drug Administration (FDA; Rockville, MD) are faced with making policy changes to accommodate these testing needs. Any loosening of regulatory requirements in the area of clinical trials for vaccines and therapeutics is a boon to industry, but proposed changes are unlikely to apply to common diseases. However, some government officials are viewing the vaccines as "orphan" products in order to stimulate industry interest in producing them.

Perhaps most striking among the changes being contemplated is the FDA-proposed "animal efficacy rule." This pending rule, which officials expect to finalize later this year, specifically addresses product evaluations for vaccines intended to prevent infectious diseases, such as smallpox or anthrax, for which clinical trials "to test efficacy could not be done," says Kathryn Zoon, director of the FDA Center for Biologics Evaluation and Research (CBER).

Hence, FDA will plan "to use animal efficacy data when approving such products," Zoon says. In most cases, the agency will require efficacy evaluations among more than one animal species, with biological responses being "reproducible" across different species. However, because "safety can't be short-changed," she says, producers will still be expected to provide conventional data to show that such vaccines are both safe and immunogenic, based on testing of candidate products in human volunteers.

"The [FDA] does take a flexible view allowing use of surrogate endpoints, and its fast-track proposal allows them to approve products based on surrogate endpoints, as they do with AIDS drugs," says Alan Goldhammer of the Biotechnology Industry Organization (BIO; Washington, DC). "However, I would be surprised if FDA were to extend this policy to vaccines [for diseases] of general prevalence in society."

FDA plans to use animal efficacy data for approving vaccines against such rare diseases as anthrax. (Bacillus anthracis shown above)

Anthrax and smallpox are "the two at the top" of the list of most likely bioterrorist threats, says Donald Henderson, who directs the Johns Hopkins University Center for Civilian Biodefense Studies (CBS; Baltimore, MD) and is a former associate director of the White House Office of Science and Technology Policy. However, finding markets for—let alone testing the vaccine efficacy of—products intended to protect against either of these deadly diseases will not be entirely straightforward, says Margaret Hamburg, assistant secretary for planning and evaluation in the Department of Health and Human Services (HHS; Washington, DC).

Therefore, Hamburg and other HHS officials also are seeking ways to stimulate renewed interest from industry in developing such products. In a way, these vaccines seem "akin to orphan drugs," she says. "For smallpox, there is no disease, and it's not clear what the market is, although my guess is that down the road it will be enormous." However, negotiating with industry as to how to develop and fairly price such products "won't be an easy road," she adds. "It will require a humanitarian spirit to work on this process."

The last case of human smallpox from natural causes was reported in 1977, meaning there is no way to conduct even field trials to evaluate a new smallpox vaccine, Henderson points out. Moreover, the relative rarity of naturally transmitted anthrax infections again means that vaccine field-testing is all but impossible.

"There's no question that these are things the agency can do in the name of national security," says Goldhammer, referring to the "animal efficacy" proposal. "There are companies working on vaccines for the military [Nat. Biotechnol. 16, 327, 1998], and this policy is vital to both the military and the companies." Thus, he says, the proposed "FDA policy is necessary and welcome. You can't do these trials in any other way."

Although there are vaccines to protect against both smallpox and anthrax, the quality and supply are problematic, according to public health experts who are considering bioterrorism preparedness issues. The anthrax vaccine "contains extraneous protein" and is "not highly purified," making it desirable to develop a "second-generation vaccine made by modern technology for the national stockpile," says Philip Russell, a former director of the US Army Medical Research Institute of Infectious Diseases (Frederick, MD). However, "there is no product development program underway." And stockpiles of the conventional smallpox vaccine, maintained in the United States and Europe, are considered "inadequate and deteriorating." They are associated with nasty side effects, particularly among immunocompromised recipients, says Russell.

The Defense Department, which plans to reintroduce smallpox vaccinations (and already is inoculating its forces with available anthrax vaccine), is developing a second-generation smallpox vaccine produced on cell culture, according to Russell. However, to validate this vaccine through means of limited human trials, officials face another "obstacle" because of the short supply of smallpox-specific immunoglobulin, a product that helps to protect vaccine recipients against side effects. "We can't do clinical testing without this," he says.

Defense officials also are moving ahead because this newer vaccine could be useful for meeting the needs for protecting the civilian population (emergency and health care personnel or even exposed population groups, for instance), according to Russell. "But first we need to overcome bureaucratic obstacles and put this on a fast track."