Adjusting FDA policies to address bioterrorist threat
Jeffrey L. Fox
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."
