Use of surrogate markers for drugs of military importance

Abstract

In the future, U.S. military forces will be faced with opposing forces that have chemical and biological weapon capabilities. Although drugs used against these agents would be an ideal solution to protecting soldiers, the ability to test their efficacy in humans is limited by several ethical and technical problems: (1) the high risk of toxicity to volunteers; (2) the risk of delayed side effects in the volunteers; and (3) the inability to extrapolate effects against sublethal doses to efficacy against lethal doses. The Food and Drug Administration (FDA) relies on safety and efficacy data in humans, making approval for these types of drugs difficult. An alternative approach for regulatory approval would be to use surrogate markers. Surrogate markers are biochemical or physiologic measurements that demonstrate the direct effect of the drug. Surrogate markers, such as CD4 counts and viral RNA levels, have been used recently in the anti-human immunodeficiency virus drug approval process with success. A drug development program using surrogate markers must meet several criteria, including demonstrated efficacy in animal models, correlation between efficacy and the surrogate marker, a link between the surrogate marker and the pathophysiology and toxicologic effects of the agent, and the ability to produce the surrogate marker in humans. This article illustrates the use of drug-induced methemoglobin as a surrogate marker for protection against cyanide intoxication. Safety issues regarding this class of drugs would also have to be pursued aggressively during and after their use by military forces. Demonstrating that the drug satisfies these criteria would be a platform for approval by the FDA. The guidelines mentioned above should be an acceptable approach for FDA approval, scientific researchers, medical practitioners, and the soldiers using these drugs.