Drugs approved on basis of animal studies should be last option’

FDA amends rule to respond to possibility of bioterrorist agents

The Food and Drug Administration (FDA) now can approve new drugs and biologics for use based on evidence of effectiveness from appropriate animal studies. The FDA took the action to respond to the need for adequate medical responses to protect or treat individuals exposed to lethal or permanently disabling toxic substances or organisms.

But one pharmacist says he hopes that any drug that falls under the new amended drug and biological product regulations would be used as a last option only. "Until we actually treat someone who is exposed to a particular toxin, we don’t know whether it works or not. It’s difficult to consider something like that a first-line therapy," says Kenneth Rockwell Jr., PharmD, MS, director of the Investigational Drug Service at the University of Pennsylvania in Philadelphia. Furthermore, if the FDA approves such a drug, even for a narrow indication such as treatment for exposure to a particular biologic agent, the possibility exists that some health professionals may try to use it in other situations.

The FDA published the amendment to its drug and biological regulations in the May 31 Federal Register. The rule, which took effect June 30, applies when adequate and well-controlled clinical studies in humans cannot be ethically conducted because the studies would involve administering a potentially lethal or permanently disabling toxic substance or organism to healthy human volunteers.

Under this rule, the FDA can rely on the evidence from animal studies to provide substantial evidence of the effectiveness of these products when:

• There is a reasonably well-understood pathophysiological mechanism for the toxicity of the chemical, biological, radiological, or nuclear substance and its amelioration or prevention by the product.

• The effect is demonstrated in more than one animal species expected to react with a response predictive for humans, unless the effect is demonstrated in a single animal species that represents a sufficiently well-characterized animal model (meaning the model has been adequately evaluated for its responsiveness) for predicting the response in humans.

"Some animals will react the same way as a human, but some won’t. It’s hard for us to tell that off-hand," Rockwell says. "For example, we can’t just test it in a rat because some drugs will act the same way in rats as in humans, but some will be the complete opposite. So we try to be as safe as we can by testing it on as many different species as possible. The FDA usually recommends at least two or three unrelated species."

• The animal study endpoint is clearly related to the desired benefit in humans, which is generally enhancement of survival or prevention of major morbidity.

• The data or information on the pharmacokinetics and pharmacodynamics of the product or other relevant data or information in animals and humans is sufficiently well-understood to allow selection of an effective dose in humans, and it is therefore reasonable to expect the effectiveness of the product in animals to be a reliable indicator of its effectiveness in humans.

Rockwell says he hopes the FDA would perform some basic safety tests of the drugs and biologics in human beings first, at least with very small doses. The FDA says products evaluated for effectiveness under the new regulations will be evaluated for safety under pre-existing requirements for establishing the safety of new drug and biological products. "The safety of most of these products can be studied in human volunteers similar to the people who would be exposed to the product," the agency says in the rule.

The FDA also "recognizes that some safety data, such as data on possible adverse interactions between the toxic substance itself and the new product, may not be available. This is not expected to keep the agency from making an adequate safety evaluation." The FDA may take into account other data, including that involving humans, in assessing the sufficiency of animal data.

Will drug companies respond?

The amendment will help make sure essential new pharmaceutical products are available much sooner, says Lester M. Crawford, DVM, PhD, FDA deputy commissioner.

Rockwell, however, doesn’t foresee a lot of drug companies taking advantage of the opportunity to develop these drugs. "The use is going to be extremely limited for something so toxic that it can’t ethically be tested in humans. The drug company would never be able to use it until there was an actual attack or chemical exposure."

In that case, a federal agency, such as the Centers for Disease Control and Prevention in Atlanta, might purchase the medication and supply it to local governments. Rockwell says he hopes that such an action would tightly control the use of the agent. "If the FDA wanted to actually allow a product’s use before testing it on humans, it should be [controlled] through a very restricted system." The drug could become part of the CDC stockpile, for example, where the need for the drug could first be assessed.