helping the public get the accurate, science-based information they need to use medicines and foods to maintain and improve their health” (FDA 2010). This multifaceted charge shapes the FDA’s responsibility for the use of investigational new drugs (INDs) developed pursuant to the Federal Food, Drug, and Cosmetic (FFDC) Act, as amended by the Food and Drug Administration Modernization Act of 1997, 21 USC 301 et seq. (see 21 CFR Part 312), and the approval of new indications for previously approved substances.

During the 1990-1991 Persian Gulf War, the FDA granted waivers to the Department of Defense (DoD) for the off-label administration of pyridostigmine bromide (PB) tablets for prophylaxis against nerve agent and botulinum toxoid vaccine for prophylaxis against botulism to military personnel without research informed consent on the basis of 21 CFR Part 50 [1997]. In 1999, the FDA recognized that it would be contrary to the public interest and inconsistent with the public health purpose of the Public Health Service Act to conclude that a drug or biological product could not be approved because human efficacy trials could not be ethically or legally conducted (21 CFR Parts 314 and 601; FDA 1999). Therefore, the FDA recommended that when human efficacy trials could not be done ethically or legally, rather than leave its evaluators without a basis upon which to “fairly and responsibly” (FDA 1999, p 53964) conclude that a drug or biological product would be effective, animal studies could provide sufficient information to support a finding of “substantial evidence” that would warrant approval (p 53965). The agency suggested that it would approve a “new drug or biological product on the basis of adequate and well-controlled animal trials when it is scientifically reasonable to expect that the effect of the drug or biological product in animals is reasonably likely to predict clinical benefit in humans” (p 53964).

The FDA proposed amending its regulations to identify the information necessary to provide sufficient evidence of the “efficacy of new drug and biological products used to reduce or prevent the toxicity of chemical, biological, radiological, or nuclear substances when adequate and well-controlled efficacy studies in humans cannot be ethically conducted because they would involve administering a potentially lethal or permanently disabling toxic substance or organism to healthy human volunteers without a proven treatment and field trials (assessment of use of the product after accidental or hostile exposure to the substance) are not feasible” (FDA 1999, p 53961). It advised that in such situations “certain new drug and biological products that are intended to reduce or prevent serious or life-threatening conditions could be approved for marketing based on evidence of effectiveness derived from appropriate studies in animals, without adequate and well-controlled efficacy studies in humans” (p 53961). Safety still would be studied in human volunteers after approval and the products “would be expected to provide meaningful therapeutic benefits to patients over existing treatment” (p 53963). The agency acted under the authority of the FFDC Act in proposing amendments to 21 CFR Part 314 Subpart I (Approval of New Drugs for Use Against Lethal or Permanently Disabling Toxic Substances When Efficacy Studies in Humans Ethically Cannot Be Conducted) and Part 601 Subpart G (Approval of Biological Products for Use Against Lethal or Permanently Disabling Toxic Substances When Efficacy Studies in Humans Ethically Cannot Be Conducted).

Three years later, in 2002, the final rule provided for “approval of certain new drug and biological products based on animal data when adequate and well-controlled efficacy 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 and field trials are not feasible prior to approval. Under this rule, in these situations, certain new drug and biological products that are intended to reduce or prevent serious or life-threatening conditions can be approved for marketing based on evidence of effectiveness derived from appropriate studies in animals, without adequate and well-controlled efficacy studies in humans” (FDA 2002, p 37989).



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