FDA says pufferfish caught off Florida may contain neurotoxin

Robert Roos

Jun 4, 2002 (CIDRAP News) The Food and Drug Administration(FDA), in an effort to improve the healthcare system's ability to help thevictims of terrorist attacks, announced last week that it may approve somedrugs on the basis of efficacy testing in animals only, without human efficacystudies.

The new rule will apply when human studies of drugeffectiveness are too risky because they would require subjecting volunteers topotentially lethal or disabling toxins or pathogens, the agency said. The ruleis intended for drugs and products used to treat the effects of chemical,biological, radiological, and nuclear substances.

"The terrorist attacks of last fall underscored theacute need for this new regulation," FDA Deputy Commissioner Lester M.Crawford said in a May 30 news release. "Today's action will help makecertain essential new pharmaceutical products available much soonerthoseproducts that because of the very nature of what they are designed to treatcannot be safely or ethically tested for effectiveness in humans."

The FDA originally proposed the rule in October 1999. Thefinal rule was published in the FederalRegister May 31 and will take effect Jun30, officials said. Drugs approved under the rule will still have to be testedfor safety in humans under existing requirements.

"This rule will apply when adequate and well-controlledclinical studies in humans cannot be ethically conducted and field efficacystudies are not feasible," the FDA said. The agency will rely on evidencefrom animal studies when:

The mechanism of effects of the harmful substance or agent and the protective or remedial mechanism of the drug are "reasonably well understood"
The effect of the drug or product "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 . . . for predicting the response in humans"
Enough is known about the action of the drug to choose an effective dose for humans

In the rule, FDA states, "Approval of the use of a druglacking human evidence of effectiveness represents a significant departure fromordinary practice. There are countless examples of treatments with favorableeffects in animals that did not prove effective in humans." That is whyevidence from more than one animal species is needed to make a persuasive casefor using a drug in humans, unless the drug is effective in a species that isknown to be a good model for the human response, the agency says. The latterwill most often occur with anti-infective drugs, because "animal models formany infectious diseases have been studied for years and are very wellcharacterized," the document states.

The new rule was not adopted for the sake of any particulardrugs now on the horizon, according to the FDA. The document states,"There is no list of products that may be approved based on evidence ofeffectiveness from efficacy studies in animals. The rule provides criteria todetermine if evidence of effectiveness from efficacy studies in animals maysupport approval of a product."

Though the FDA called the approval of a drug without humanefficacy studies unusual, it is not unprecedented. In August 2000 the agencyapproved the use of ciprofloxacin for inhalational anthrax without suchstudies. Also, in November 2001, after the letter-borne anthrax attacks, theFDA said that doxycycline and penicillin G procaine could be used forpostexposure prophylaxis against inhalational anthrax. That decision was basedon studies of rhesus monkeys, other laboratory studies, and data from the 1979anthrax outbreak in Sverdlovsk in the former Soviet Union.

The new rule includes FDA responses to comments it receivedafter the rule was proposed. One person suggested dropping the requirement fora "reasonably well-understood" mechanism of action for the harmfulsubstance and the drug. This is generally not required for drugs that have beentested in humans, the report says. But in the absence of such testing,"This understanding helps provide assurance that the efficacy data forstudies in animals can be applied to humans," the FDA says, adding,"We have not specified exactly what degree of pathophysiologicunderstanding is needed, and that will be a matter of judgment."

In the final rule, the FDA dropped a proposed requirementthat self-administered drugs approved under the rule be in "unit-of-usepackaging" with attached labeling. That rule could hinder the distributionof such drugs in an emergency, officials said.

The rule requires that drugs include labeling for patientsexplaining that, for ethical or feasibility reasons, the drug was approved onthe basis of efficacy studies only in animals. However, patients will not berequired to provide informed consent, as is the case with products classifiedby the FDA as investigational new drugs.

The rule also states that companies applying for approvalunder the rule must include a plan or approach for doing postmarketing studiesif the product is used.