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Statement of Need: A distinct possibility exists that American military personnel and civilians may be exposed to lethal or permanently disabling chemical, biological, radiological, or nuclear substances in the course of conventional or unconventional warfare, as a result of terrorist actions, or as a consequence of an industrial accident. Significant difficulties are presented in conducting efficacy studies on drug and biological products intended to reduce or prevent the toxicity of these substances in humans. The incidence of exposure is so low that field efficacy studies cannot be conducted and the toxicity of the substances prevents them from being ethically given to healthy volunteers. The only practical and ethical means of evaluating the efficacy of drugs and biological products in these situations is to rely on data from animal studies that are an adequate model for the action of both the lethal or permanently disabling substance and the drug or biological product in humans.

Summary of the Legal Basis: FDA approves new drugs under the authority of the Federal, Food, Drug, and Cosmetic Act (the Act) and biological products under section 351 of the Public Health Service Act. Section 505(d) (21 USC 355(d)) of the Act authorizes the Secretary of Health and Human Services to issue an order refusing to approve a new drug application if the Secretary finds that "there is a lack of substantial evidence that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the proposed labeling thereof ...." The term "substantial evidence" is defined in section 505(d) of the Act as"... evidence consisting of adequate and well-controlled investigations, including clinical investigations, by experts qualified by scientific training and experience to evaluate the effectiveness of the drug involved, on the basis of which it could fairly and responsibly be concluded by such experts that the drug will have the effect it purports or is represented to have under the conditions of use prescribed, recommended, or suggested in the labeling or proposed labeling thereof." In interpreting the term "substantial evidence," FDA has viewed the phrase "adequate and well-controlled investigations, including clinical investigations" as meaning that efficacy determinations must include studies of efficacy in humans. The agency's regulations did not contemplate situations in which efficacy studies cannot be ethically conducted in humans, and FDA believes that it would be inconsistent with the statute's public health objectives to conclude that FDA cannot use some other basis for considering the efficacy of such products. The legislative history does not address this issue. Concluding that such products cannot ever be approved because human efficacy trials cannot be conducted is contrary to the public interest and inconsistent with the Act's purpose of public health protection. FDA has therefore concluded that, where definitive human efficacy studies cannot be ethically conducted because they would necessarily expose healthy subjects to a potentially lethal or permanently disabling substance, the statutory standard permits efficacy to be based on adequate and well-controlled investigations that are not conducted in humans. This conclusion is consistent with the recognition by Congress of the importance of ethical behavior in the study of unapproved products. For FDA to approve products where definitive efficacy studies cannot be conducted in humans there must be sufficient data available to meet the statutory standard. The data must be such that experts are able to fairly and responsibly conclude "that the drug will have the effect it purports or is represented to have ..." in humans. Where data from adequate and well-controlled animal studies meet this standard, FDA may approve the product.

Alternatives: FDA did not identify any valid alternatives to using efficacy data from animal studies to approve drug and biological products used to treat or prevent the toxicity of chemical, biological, radiological, or nuclear substances where the normal incidence of exposure is so low that normal clinical trials would be impractical and the deliberate exposure of volunteers to the substances would be unethical. The rule would not apply if product approval can be based on standards described elsewhere in FDA's regulations (for example, accelerated approval based on human surrogate markers or clinical endpoints other than survival or irreversible morbidity).

Anticipated Costs and Benefits: The potential public health benefits of having new drugs and biological products approved under this rule are difficult to measure. The cost of approving new drugs and biological products under this rule should not exceed the cost of approving similar drugs based on clinical efficacy data.

Risks: Risks from the use of drugs and biological products approved under this rule should be minimal. The safety of these products will be studied in human volunteers comparable to the people who would be exposed to the product.